Novel substituted 6,7-dihydro-5h-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof

ABSTRACT

Compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R1 and R2 represent hydrogen or deuterium atoms; R3 represents a hydrogen atom or a —COOH, a —OH or a —OPO(OH) 2  group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a —OH group; wherein at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a —COOH, —OH or —OPO(OH) 2  group, then R5 represents a hydrogen atom; when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms; and R6 is selected from an optionally substituted phenyl, heteroaryl, cycloalkyl and heterocycloalkyl group;
 
and the preparation and the therapeutic uses of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, useful especially in the treatment of cancer.

Provided herein are novel substituted 6,7-dihydro-5H-benzo[7]annulenecompounds, the processes for their preparation, as well as thetherapeutic uses thereof, in particular as anticancer agents viaselective antagonism and degradation of estrogen receptors.

The Estrogen Receptors (ER) belong to the steroid/nuclear receptorsuperfamily involved in the regulation of eukaryotic gene expression,cellular proliferation and differentiation in target tissues. ERs are intwo forms: the estrogen receptor alpha (ERα) and the estrogen receptorbeta (ERβ) respectively encoded by the ESR1 and the ESR2 genes. ERα andERβ are ligand-activated transcription factors which are activated bythe hormone estrogen (the most potent estrogen produced in the body is17β-estradiol). In the absence of hormone, ERs are largely located inthe cytosol of the cell. When the hormone estrogen binds to ERs, ERsmigrate from the cytosol to the nucleus of the cell, form dimers andthen bind to specific genomic sequences called Estrogen ResponseElements (ERE). The DNA/ER complex interacts with co-regulators tomodulate the transcription of target genes.

ERα is mainly expressed in reproductive tissues such as uterus, ovary,breast, bone and white adipose tissue. Abnormal ERα signaling leads todevelopment of a variety of diseases, such as cancers, metabolic andcardiovascular diseases, neurodegenerative diseases, inflammationdiseases and osteoporosis.

ERα is expressed in not more than 10% of normal breast epithelium butapproximately 50-80% of breast tumors. Such breast tumors with highlevel of ERα are classified as ERα-positive breast tumors. Theetiological role of estrogen in breast cancer is well established andmodulation of ERα signaling remains the mainstay of breast cancertreatment for the majority ERα-positive breast tumors. Currently,several strategies for inhibiting the estrogen axis in breast cancerexist, including: 1—blocking estrogen synthesis by aromatase inhibitorsthat are used to treat early and advanced ERα-positive breast cancerpatients; 2—antagonizing estrogen ligand binding to ERα by tamoxifenwhich is used to treat ERα-positive breast cancer patients in both pre-and post-menopausal setting; 3—antagonizing and downregulating ERαlevels by fulvestrant, which is used to treat breast cancer in patientsthat have progressed despite endocrine therapies such as tamoxifen oraromatase inhibitors.

Although these endocrine therapies have contributed enormously toreduction in breast cancer development, about more than one-third ofERα-positive patients display de-novo resistance or develop resistanceover time to such existing therapies. Several mechanisms have beendescribed to explain resistance to such hormone therapies. For example,hypersensitivity of ERα to low estrogen level in treatment witharomatase inhibitors, the switch of tamoxifen effects from antagonist toagonist effects in tamoxifen treatments or multiple growth factorreceptor signaling pathways. More recently, acquired mutations in ERαoccurring after initiation of hormone therapies may play a role intreatment failure and cancer progression. Certain mutations in ERα,particularly those identified in the Ligand Binding Domain (LBD), resultin the ability to bind to DNA in the absence of ligand and conferhormone independence in cells harboring such mutant receptors.

Most of the endocrine therapy resistance mechanisms identified rely onERα-dependent activity. One of the new strategies to counterforce suchresistance is to shut down the ERα signaling by removing ERα from thetumor cells using Selective Estrogen Receptors degraders (SERDs).Clinical and preclinical data showed that a significant number of theresistance pathways can be circumvented by the use SERDs.

There is still a need to provide SERDs with good degradation efficacy.

G. M. Anstead et al. have described 2,3-diarylindenes and2,3-diarylindenones as binders of estrogen receptors (Journal ofMedicinal Chemistry, 1988, Vol. 31, No. 7, p. 1316-1326).

R. McCague et al. have described analogues of (Z)- and(E)-4-hydroxytamoxifen and have tested their binding affinities toestrogen receptors (Journal of Medicinal Chemistry, 1998, Vol. 31, No.7, p. 1285-1290).

Provided herein are novel compounds able to selectively antagonize anddegrade the estrogen receptors (SERDs compounds), for use in cancertreatment.

Provided herein are compounds of the formula (I):

wherein:

-   -   R1 and R2 represent independently a hydrogen atom or a deuterium        atom;    -   R3 represents a hydrogen atom, a —COOH group, a —OH group or a        —OPO(OH)₂ group;    -   R4 represents a hydrogen atom or a fluorine atom;    -   R5 represents a hydrogen atom or a —OH group;    -   wherein:        -   at least one of R3 or R5 is different from a hydrogen atom;        -   when R3 represents a —COOH group, a —OH group or a —OPO(OH)₂            group, then R5 represents a hydrogen atom;        -   when R5 represents a —OH group, then R3 and R4 represent            hydrogen atoms;    -   R6 is selected from:        -   a phenyl group or a heteroaryl group comprising 3 to 9            carbon atoms and comprising from 1 to 3 heteroatoms            independently selected from oxygen, nitrogen and sulphur,            said phenyl and heteroaryl groups being unsubstituted or            substituted with 1 to 3 substituents independently selected            from: a (C₁-C₆)-alkyl group unsubstituted or substituted            with one or more (such as 1, 2 or 3) fluorine atoms; a            halogen atom; a —OH group; a (C₁-C₆)-alkoxy group            unsubstituted or substituted with one or more (such as 1, 2            or 3) fluorine atoms; a cyano group; a sulphur group            substituted with 5 fluorine atoms or (C₁-C₆)-alkyl groups            substituted with two or more (such as 2 or 3) fluorine            atoms; a sulfonyl-(C₁-C₆)-alkyl group wherein said            (C₁-C₆)-alkyl group are unsubstituted or substituted with            two or more (such as 2 or 3) fluorine atoms; a silane group            substituted with 3 (C₁-C₆)-alkyl groups; an amine group            unsubstituted or substituted with one or more (such as 1            or 2) (C₁-C₆)-alkyl groups; an amide group unsubstituted or            substituted with one or more (such as 1 or 2) (C₁-C₆)-alkyl            groups; a heterocycloalkyl group saturated or partially            saturated, comprising 3 to 5 carbon atoms and comprising 1            or 2 heteroatoms independently selected from oxygen,            nitrogen and sulphur; or a heteroaryl group comprising 2 to            4 carbon atoms and comprising 1 to 3 heteroatoms selected            from oxygen, nitrogen and sulphur and being unsubstituted or            substituted with an oxo group;        -   a cycloalkyl group or a heterocycloalkyl group comprising 4            to 9 carbon atoms and comprising 1 or 2 heteroatoms            independently selected from oxygen, nitrogen and sulphur,            said cycloalkyl or heterocycloalkyl groups being saturated            or partially saturated and being unsubstituted or            substituted with 1 to 4 substituents independently selected            from:    -   a fluorine atom; a —OH group; a (C₁-C₆)-alkyl group; a —COOR7        group wherein R7 is a (C₁-C₆)-alkyl group; and an oxo group.

The compounds of formula (I) contain one or more asymmetric carbonatoms, more particularly one asymmetric carbon atom on the pyrrolydinylgroup. They may therefore exist in the form of enantiomers. Thecompounds of formula (I) include enantiomers, racemates, and mixturesthereof. (In particular, the carbon 3 of the pyrrolidinyl group linkedto the oxygen atom of the formula (I) may be in the absoluteconfiguration (R) or (S). The carbon 3 of the pyrrolidinyl group isadvantageously in the absolute configuration (S).

The compounds of formula (I) also include tautomer forms thereof.

The compounds of formula (I) may exist in the form of bases, acids, orzwitterions.

The compounds of formula (I) can be in the form of addition salts withacids or bases. Hence, provided herein inter alia, are compounds offormula (I) or to pharmaceutically acceptable salts thereof.

These salts may be prepared with pharmaceutically acceptable acids orbases, although the salts of other acids or bases useful, for example,for purifying or isolating the compounds of formula (I) are provided.

As used herein, the terms below have the following definitions unlessotherwise mentioned throughout the instant specification:

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine        atom;    -   an oxo: a “═O” group;    -   a cyano group: a “—C≡N” group;    -   an amine group: a nitrogen atom unsubstituted or substituted        with one or more (C₁-C₆)-alkyl groups;    -   an amide group: a —C(O)NH₂ group wherein the nitrogen atom can        be unsubstituted or substituted with one or more (C₁-C₆)-alkyl        groups;    -   a silane group: a silicon atom substituted with 3 (C₁-C₆)-alkyl        groups;    -   an alkyl group: a linear or branched saturated hydrocarbon-based        aliphatic group comprising, unless otherwise mentioned, from 1        to 6 carbon atoms (noted “(C₁-C₆)-alkyl”). By way of examples,        mention may be made of, but not limited to: methyl, ethyl,        propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,        tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, and        the like;    -   an alkoxy group: an —O-alkyl group where the alkyl group is as        previously defined.        By way of examples, mention may be made of, but not limited to:        methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or        tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, and the        like;    -   a cycloalkyl group: a cyclic alkyl group comprising, unless        otherwise mentioned, from 3 to 6 carbon atoms, saturated or        partially unsaturated and unsubstituted or substituted. By way        of examples, mention may be made of, but not limited to:        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl        groups, and the like;    -   a heterocycloalkyl group: a cyclic alkyl group comprising,        unless otherwise mentioned, from 3 to 6 carbon atoms and        containing 1 or 2 heteroatoms such as oxygen, nitrogen or        sulphur. Such nitrogen atom may be substituted by an oxygen atom        in order to form a —N—O bond. Such —N—O bond can be in a form of        a N-oxide (—N⁺—O⁻). Such heterocycloalkyl group may be saturated        or partially saturated and unsubstituted or substituted and may        be monocyclic or bicyclic.

By way of examples of monocyclic heterocycloalkyl groups, mention may bemade of, but not limited to: tetrahydropyridinyl, dihydropyridinyl,dihydropyranyl, tetrahydropyranyl groups, and the like.

A bicyclic heterocycloalkyl group means: a phenyl group fused to amonocyclic heterocycloalkyl group as defined above. By way of examplesof bicyclic heterocycloalkyl groups, mention may be made of, but notlimited to: tetrahydroquinolinyl, indolinyl, benzodioxolyl,dihydrobenzodioxinyl, dihydrobenzoxazinyl, benzofuranyl groups, alloptionally substituted as above indicated, and the like.

-   -   A heteroaryl group: a cyclic aromatic group containing between 4        and 9 carbon atoms and containing between 1 and 3 heteroatoms,        such as nitrogen, oxygen or sulphur. Such nitrogen atom may be        substituted by an oxygen atom in order to form a —N—O bond. Such        —N—O bond can be in a form of a N-oxide (—N⁺—O⁻). Said        heteroaryl group may be monocyclic or bicyclic. By way of        examples of heteroaryl groups, mention may be made of, but not        limited to: isoxazole, pyridine, pyrimidine, benzotriazole,        benzoxazole, pyrrolo[2,3-b]pyridine, benzimidazole,        benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran,        indole, quinolyl, indazole, benzisoxazole, benzisothiazole        groups and the like;    -   A zwitterion: a globally neutral molecule with a positive and a        negative electrical charge and having an acid group and a basic        group. By way of examples, mention may be made of, but not        limited to compounds of formula (I) having R3 which represents a        —COOH group or an —OPO(OH)₂ group.

In an embodiment, in the compounds of formula (I), R1 and R2 representhydrogen atoms.

In another embodiment, in the compounds of formula (I), R1 and R2represent deuterium atoms.

In another embodiment, in the compounds of formula (I), R3 represents ahydrogen atom.

In another embodiment, in the compounds of formula (I), R3 represents a—COOH group.

In another embodiment, in the compounds of formula (I), R3 represents a—OH group.

In another embodiment, in the compound of formula (I), R3 represents a—COOH group or a —OH group.

In another embodiment, in the compounds of formula (I), R3 represents a—OPO(OH)₂ group.

In another embodiment, in the compounds of formula (I), R4 represents ahydrogen atom.

In another embodiment, in the compounds of formula (I), R4 represents afluorine atom.

In another embodiment, in the compounds of formula (I), R5 represents ahydrogen atom.

In another embodiment, in the compounds of formula (I), R5 represents a—OH group.

In another embodiment, in the compounds of formula (I) R6 is selectedfrom a phenyl group unsubstituted or substituted with 1 to 3substituents independently selected from: a (C₁-C₆)-alkyl groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a halogen atom; a —OH group; a (C₁-C₆)-alkoxy groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a cyano group; a sulphur group substituted with 5fluorine atoms or (C₁-C₆)-alkyl groups substituted with two or more(such as 2 or 3) fluorine atoms; a sulfonyl-(C₁-C₆)-alkyl group whereinsaid (C₁-C₆)-alkyl group are unsubstituted or substituted with two ormore (such as 2 or 3) fluorine atoms; a silane group substituted with 3(C₁-C₆)-alkyl groups; an amine group unsubstituted or substituted withone or more (such as 1 or 2) (C₁-C₆)-alkyl groups; an amide groupunsubstituted or substituted with one or more (such as 1 or 2)(C₁-C₆)-alkyl groups; a heterocycloalkyl group saturated or partiallysaturated, comprising 3 to 5 carbon atoms and comprising 1 or 2heteroatoms independently selected from oxygen, nitrogen and sulphur;and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1to 3 heteroatoms selected from oxygen, nitrogen and sulphur and beingunsubstituted or substituted with an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a phenyl group unsubstituted or substituted with 1 to 3substituents independently selected from: a (C₁-C₆)-alkyl groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a halogen atom; a —OH group; a (C₁-C₆)-alkoxy groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a cyano group; a sulphur group substituted with 5fluorine atoms or (C₁-C₆)-alkyl groups substituted with two or more(such as 2 or 3) fluorine atoms; a sulfonyl-(C₁-C₆)-alkyl group whereinsaid (C₁-C₆)-alkyl group are unsubstituted or substituted with two ormore (such as 2 or 3) fluorine atoms; a silane group substituted with 3(C₁-C₆)-alkyl groups; an amide group unsubstituted or substituted withone or more (such as 1 or 2) (C₁-C₆)-alkyl groups; a heterocycloalkylgroup saturated or partially saturated, comprising 3 to 5 carbon atomsand comprising 1 or 2 heteroatoms independently selected from oxygen,nitrogen and sulphur, and a heteroaryl group comprising 2 to 4 carbonatoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogenand sulphur and being unsubstituted or substituted with an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a phenyl group unsubstituted or substituted with 1 to 3substituents independently selected from: a (C₁-C₃)-alkyl groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a halogen atom; a —OH group; a (C₁-C₃)-alkoxy groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a cyano group; a sulphur group substituted with 5fluorine atoms or (C₁-C₃)-alkyl groups substituted with two or more(such as 2 or 3) fluorine atoms; a sulfonyl-(C₁-C₃)-alkyl group whereinsaid (C₁-C₃)-alkyl group are unsubstituted or substituted with two ormore (such as 2 or 3) fluorine atoms; a silane group substituted with 3(C₁-C₃)-alkyl groups; an amide group unsubstituted or substituted withone or more (such as 1 or 2) (C₁-C₃)-alkyl groups; a heterocycloalkylgroup saturated or partially saturated, comprising 3 to 5 carbon atomsand comprising 1 or 2 heteroatoms independently selected from oxygen,nitrogen and sulphur, and a heteroaryl group comprising 2 to 4 carbonatoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogenand sulphur and being unsubstituted or substituted with an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a phenyl group unsubstituted or substituted with 1 to 3substituents independently selected from: a methyl group; an ethylgroup; an isopropyl group; a tert-butyl group; a —CHF₂ group; a —CF₃group; a —CF₂CH₃ group; a chlorine atom; a fluorine atom; a —OH group; a—OCH₃ group; a —OCH₂CH₃ group; a —OCH₂CH₂F group; a —OCHF₂ group; a—OCH₂CHF₂ group; a —OCF₃ group; a —OCH₂CF₃ group; a cyano group; a—SCHF₂ group; a —SCF₃ group; a —SF₅ group; a —SO₂CH₃ group; a —SO₂CF₃group; a —Si(CH₃)₃ group; an oxetane group; a piperidine group; amorpholine group; a pyrrolidine group and a triazolone group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom an unsubstituted or substituted phenyl group selected from thefollowing list:

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a heteroaryl group comprising 3 to 9 carbon atoms and comprisingfrom 1 to 3 heteroatoms independently selected from oxygen, nitrogen andsulphur, said heteroaryl group being unsubstituted or substituted with 1to 3 substituents independently selected from: a (C₁-C₆)-alkyl groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a halogen atom; a —OH group; a N-oxide (—N⁺—O⁻), a(C₁-C₆)-alkoxy group unsubstituted or substituted with one or more (suchas 1, 2 or 3) fluorine atoms; a cyano group; a sulphur group substitutedwith 5 fluorine atoms or (C₁-C₆)-alkyl groups substituted with two ormore (such as 2 or 3) fluorine atoms; a sulfonyl-(C₁-C₆)-alkyl groupwherein said (C₁-C₆)-alkyl group being unsubstituted or substituted withtwo or more (such as 2 or 3) fluorine atoms; a silane group substitutedwith 3 (C₁-C₆)-alkyl groups; an amine group unsubstituted or substitutedwith one or more (such as 1 or 2) (C₁-C₆)-alkyl groups; an amide groupunsubstituted or substituted with one or more (such as 1 or 2)(C₁-C₆)-alkyl groups; a heterocycloalkyl group saturated or partiallysaturated, comprising 3 to 5 carbon atoms and comprising 1 or 2heteroatoms independently selected from oxygen, nitrogen and sulphur;and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1to 3 heteroatoms selected from oxygen, nitrogen and sulphur and beingunsubstituted or substituted with an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a heteroaryl group comprising 3 to 9 carbon atoms and comprisingfrom 1 to 3 heteroatoms independently selected from oxygen, nitrogen andsulphur, said heteroaryl group being unsubstituted or substituted with 1to 3 substituents independently selected from: a (C₁-C₆)-alkyl groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a halogen atom; a —OH group; a (C₁-C₆)-alkoxy groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; and an amine group unsubstituted or substituted with oneor more (such as 1 or 2) (C₁-C₆)-alkyl groups.

In another embodiment, the compounds of formula (I), R6 is selected froma heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1to 3 heteroatoms independently selected from oxygen, nitrogen andsulphur, said heteroaryl group being unsubstituted or substituted with 1to 3 substituents independently selected from: a (C₁-C₃)-alkyl groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; a halogen atom; a —OH group; a (C₁-C₃)-alkoxy groupunsubstituted or substituted with one or more (such as 1, 2 or 3)fluorine atoms; and an amine group unsubstituted or substituted with oneor more (such as 1 or 2) (C₁-C₃)-alkyl groups.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a heteroaryl group comprising 3 to 9 carbon atoms and comprisingfrom 1 to 3 heteroatoms independently selected from oxygen, nitrogen andsulphur, said heteroaryl group being unsubstituted or substituted with 1to 3 substituents independently selected from: a methyl group; a —CF₃group; a chlorine atom; a fluorine atom; a —OH group; a —OCH₃ group; a—OCH₂CH₃ group; a —OCHF₂ group; and a —NH₂ group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom an unsubstituted or substituted heteroaryl group selected from thefollowing list:

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a (C₁-C₆)-cycloalkyl group saturated or partially saturated andunsubstituted or substituted with 1 or 2 substituents independentlyselected from: a fluorine atom; a —OH group; a (C₁-C₆)-alkyl group; a—COOR7 group wherein R7 is a (C₁-C₆)-alkyl group; and an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a (C₁-C₆)-cycloalkyl group saturated or partially saturated andunsubstituted or substituted with 1 or 2 substituents independentlyselected from: a fluorine atom; a —OH group; a (C₁-C₃)-alkyl group; a—COOR7 group wherein R7 is a (C₁-C₃)-alkyl group; and an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a (C₁-C₆)-cycloalkyl group saturated or partially saturated,unsubstituted or substituted with 1 or 2 substituents independentlyselected from: a fluorine atom or a —OH group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a substituted (C₁-C₆)-cycloalkyl group selected from the followinglist:

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a heterocycloalkyl group comprising 4 to 9 carbon atoms andcomprising 1 or 2 heteroatoms independently selected from oxygen,nitrogen and sulphur, said heterocycloalkyl group being saturated orpartially saturated and being unsubstituted or substituted with 1 to 4substituents independently selected from: a fluorine atom; a —OH group;a (C₁-C₆)-alkyl group; a —COOR7 group wherein R7 is an (C₁-C₆)-alkylgroup; and an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom:

-   -   a monocyclic-(C₁-C₆)-heterocycloalkyl group comprising one        heteroatom selected from oxygen, nitrogen and sulphur, said        monocyclic heterocycloalkyl group being saturated or partially        saturated and being unsubstituted or substituted with 1 or 2        substituents independently selected from: a (C₁-C₆)-alkyl group        and a —COOR7 group wherein R7 is an (C₁-C₆)-alkyl group or    -   a bicyclic heterocycloalkyl group comprising 8 to 9 carbon atoms        and comprising 1 or 2 heteroatoms independently selected from        oxygen, nitrogen and sulphur, said bicyclic heterocycloalkyl        group being saturated or partially saturated and being        unsubstituted or substituted with 1 to 4 substituents        independently selected from: a fluorine atom; a (C₁-C₆)-alkyl        group; a —COOR7 group wherein R7 is an (C₁-C₆)-alkyl group; and        an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom:

-   -   a monocyclic-(C₁-C₆)-heterocycloalkyl group comprising one        heteroatom selected from oxygen, nitrogen and sulphur, said        monocyclic heterocycloalkyl group being saturated or partially        saturated and being unsubstituted or substituted with 1 or 2        substituents independently selected from: a (C₁-C₃)-alkyl group        and a —COOR7 group wherein R7 is an (C₁-C₄)-alkyl group or    -   a bicyclic heterocycloalkyl group comprising 8 to 9 carbon atoms        and comprising 1 or 2 heteroatoms independently selected from        oxygen, nitrogen and sulphur, said bicyclic heterocycloalkyl        group being saturated or partially saturated and being        unsubstituted or substituted with 1 to 4 substituents        independently selected from: a fluorine atom; a (C₁-C₃)-alkyl        group; a —COOR7 group wherein R7 is an (C₁-C₄)-alkyl group; and        an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom:

-   -   a monocyclic (C₁-C₆)-heterocycloalkyl group comprising one        heteroatom selected from oxygen, nitrogen and sulphur, said        monocyclic heterocycloalkyl group being saturated or partially        saturated and being unsubstituted or substituted with 1 or 2        substituents independently selected from: a methyl group and a        —COO-tert butyl group or    -   a bicyclic heterocycloalkyl group comprising 8 to 9 carbon atoms        and comprising 1 or 2 heteroatoms independently selected from        oxygen, nitrogen and sulphur, said bicyclic heterocycloalkyl        group being saturated or partially saturated and being        unsubstituted or substituted with 1 to 4 substituents        independently selected from: a fluorine atom; a methyl group; an        ethyl group; a —COO-tert butyl group; and an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a monocyclic (C₁-C₆)-heterocycloalkyl group comprising oneheteroatom selected from oxygen, nitrogen and sulphur, said monocyclic(C₁-C₆)-heterocycloalkyl group being saturated or partially saturatedand being unsubstituted or substituted with 1 or 2 substituentsindependently selected from: a methyl group and a —COO-tert butyl group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom an unsubstituted or substituted monocyclic (C₁-C₆)-heterocycloalkylgroup selected from the following list:

In another embodiment, in the compounds of formula (I), R6 is selectedfrom a bicyclic heterocycloalkyl group comprising 8 to 9 carbon atomsand comprising 1 or 2 heteroatoms independently selected from oxygen,nitrogen and sulphur, said bicyclic heterocycloalkyl group beingsaturated or partially saturated and being unsubstituted or substitutedwith 1 to 4 substituents independently selected from: a fluorine atom; amethyl group; an ethyl group; a —COO-tert butyl group; and an oxo group.

In another embodiment, in the compounds of formula (I), R6 is selectedfrom an unsubstituted or substituted bicyclic heterocycloalkyl groupselected from the following list:

The compounds of formula (I) include the compounds having anycombination of the above-defined embodiments for R1, R2, R3, R4, R5 andR6 with each other.

Among the compounds of formula (I), mention may be made in particular ofthe following compounds:

-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-3-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-3-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol;-   6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-3-ol;-   6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-chloro-2-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-chloro-3-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-fluoro-4-hydroxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-fluoro-4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-3-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-fluoro-2-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-6-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-indolin-5-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-chloro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   tert-butyl    4-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-2-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(benzofuran-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-fluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methyl-1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,3-dimethylphenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-2-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-fluoro-2-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-chloro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-fluoro-2-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-fluoro-2-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-chloro-4-ethoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   1-fluoro-6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-2-methyl-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,4-dichlorophenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-fluoro-3-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(4-ethoxy-2,3-difluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-3-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(1,3-benzoxazol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-isopropylphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(o-tolyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-chlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   2-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-5-methoxy-benzonitrile;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-2,5-difluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid hydrochloride;-   6-(2,4-dimethoxyphenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-methoxy-2-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2-methyl-4-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[6-(trifluoromethyl)-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-2-fluoro-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-tert-butylphenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,4-tetrahydroquinolin-6-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-ethoxyphenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-methoxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(5-chloro-6-ethoxy-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-ethylphenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methoxypyrimidin-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2-(trifluoromethyl)pyrimidin-5-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   2-fluoro-4-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]benzonitrile;-   6-(5-chloro-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[6-(difluoromethoxy)-3-pyridyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,5-difluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-chloro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(5-fluoro-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-4-methyl-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2,5-dimethyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,3-difluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethylsulfanyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-chloro-4-ethoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(5-methyl-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-2-methyl-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,2-dimethyl-3H-benzofuran-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(5-chloro-6-methoxy-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-2,5-dimethyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-5-methyl-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol-   6-(5-fluoro-6-methoxy-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-chloro-4-ethoxy-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-fluoro-6-methoxy-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3,5-difluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(1-ethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methoxy-4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-5-methyl-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-fluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,4-difluoro-3-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-3-methyl-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)-2-fluoro-phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2-fluoro-4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,6-dichloro-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-3,5-difluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chloro-2-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-chloro-3-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-6-[2-methyl-4-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-2-methyl-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methylindol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-chloro-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   2-fluoro-4-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-N-methyl-benzamide;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2-fluoro-6-(trifluoromethyl)-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(2-fluoroethoxy)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-ethoxy-2,3-dimethyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[6-ethoxy-5-(trifluoromethyl)-3-pyridyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methyl-2,3-dihydro-1,4-benzoxazin-7-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   4-ethyl-6-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-1,4-benzoxazin-3-one;-   6-[2-chloro-4-(trifluoromethoxy)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)-3,5-difluoro-phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-tert-butylphenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-4-methyl-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3-chloro-4-ethoxy-5-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-aminopyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethyl)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)phenyl]-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[3,5-difluoro-4-(trifluoromethoxy)    phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)-2-methyl-phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-4-methyl-1,4-benzoxazin-3-one;-   6-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-4H-1,4-benzoxazin-3-one;-   6-(2,3-dichloro-4-ethoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[3-methyl-4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[3-chloro-4-(trifluoromethoxy)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(5-quinolyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[2-chloro-6-(trifluoromethyl)-3-pyridyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   tert-butyl    6-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-2,    3-dihydro-1,4-benzoxazine-4-carboxylate;-   6-[4-(difluoromethylsulfanyl)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,4-tetrahydroquinolin-7-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-6-[2-fluoro-4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethylsulfanyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,4-dichloro-5-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)    phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl] dihydrogen phosphate;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(5-methylisoxazol-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethylsulfonyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol    hydrochloride;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[2-fluoro-4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-isoxazol-4-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(6-ethoxy-5-fluoro-3-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-fluoro-5-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]pyridin-2-ol;-   6-(6-tert-butyl-2-fluoro-4-pyridyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-trimethylsilylphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid hydrochloride;-   6-(1,3-benzothiazol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methyl-1H-benzimidazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethylsulfanyl)phenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(1,3-benzothiazol-6-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-methylbenzotriazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[2-chloro-4-(trifluoromethoxy)    phenyl]-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-tert-butyl-2-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-fluoro-4-methylsulfonyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-methylisoxazol-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(pentafluoro-sulfanyl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-morpholinophenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methylbenzimidazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(1,2-benzoxazol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyridin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-pyrrolidin-1-ylphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methyl-1,3-benzoxazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methyl-1,3-benzoxazol-6-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,1,3-benzoxadiazol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2,1,3-benzothiadiazol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(oxetan-3-yl)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(1,2-benzothiazol-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[2,3-difluoro-4-(1-piperidyl)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(1,3-benzoxazol-6-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(1,2-benzoxazol-6-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-[4-(1,1-difluoroethyl)phenyl]-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(3,6-dihydro-2H-pyran-4-yl)-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-tetrahydropyran-4-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(3-methylbenzimidazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   4-[4-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]phenyl]-1H-1,2,4-triazol-5-one;-   6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4,4-difluorocyclohexyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(4-chlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(2-chlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(2,4-dichlorophenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(4-chloro-2-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)    pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic    acid;-   9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ol;-   5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol;-   6-(2-Chloro-3-fluoro-phenyl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic    acid;-   5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocycloheptene-2-carboxylic    acid;-   6-Benzooxazol-5-yl-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic    acid; and-   6-[4-(1,1-Difluoro-ethyl)-phenyl]-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

Another embodiment is a compound selected from the above list, or apharmaceutically acceptable salt thereof, for use in therapy, especiallyas an inhibitor and degrader of estrogen receptors.

Another embodiment is a compound selected from the above list, or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, especially breast cancer.

Another embodiment is a method of treating cancer, comprisingadministering to a subject in need thereof, in particular a human, atherapeutically effective amount of a compound selected from the abovelist, or a pharmaceutically acceptable salt thereof.

Another embodiment is a pharmaceutical composition comprising as activeprinciple an effective dose of a compound selected from the above list,or a pharmaceutically acceptable salt thereof, and also at least onepharmaceutically acceptable excipient.

The compounds of the formula (I) can be prepared by the followingprocesses.

The compounds of the formula (I) and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed below or otherwise known by the skilled person in the art. Inaddition, solvents, temperatures and other reaction conditions presentedbelow may vary as deemed appropriate to the skilled person in the art.

General below methods for the preparation of compounds of formula (I)are optionally modified by the use of appropriate reagents andconditions for the introduction of the various moieties found in thecompound of formula (I) as described below.

The following abbreviations and empirical formulae are used:

-   AcOEt ethyl acetate-   AlCl₃ aluminium trichloride-   Boc tert-butyloxycarbonyl-   P(Ph)₂-(CH₂)₃—P(Ph)₂ 1,3-bis(diphenylphosphino)propane-   Ph₃P═O triphenylphosphine oxide-   Cs₂CO₃ cesium carbonate-   CO carbon monoxide-   DCM dichloromethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EDCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et₃N triethylamine-   EtOH ethanol-   Et₂O diethyl ether-   Hal halogen atom-   HCl hydrogen chloride-   HPLC high-performance liquid chromatography-   K₂CO₃ potassium carbonate-   LCMS liquid chromatography/mass spectrometry-   LiAlD₄ lithium aluminum deuteride-   Lutidine 2,6-dimethyl-pyridine-   MeOH methanol-   MgSO₄ magnesium sulfate-   NaOH sodium hydroxide-   NaCl sodium chloride-   NaHCO₃ sodium bicarbonate-   Na₂SO₄ sodium sulfate-   NH₄H₂PO₄ ammonium dihydrogen phosphate-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   Pd(OAc)₂ palladium acetate-   Pd(dppf)Cl₂    1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Tf₂O triflic anhydride-   THF tetrahydrofuran-   ° C. degrees Celsius-   RT room temperature-   min minute(s)-   mL millilitre(s)-   mmol millimole(s)-   μmol micromole(s)-   μM micromolar-   nM nanomolar-   ppm parts per million-   SCX strong cation exchange-   HIC hydrophobic interaction column

According to SCHEME 1, in which R1, R2, R3, R4, R5 and R6 are defined asdescribed above, a substituted5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene intermediate (A) isconverted in STEP 1 into the corresponding enol triflate intermediate(B) by treatment for example with triflic anhydride (Tf₂O) in solutionin dichloromethane (DCM) in the presence of a base, for examplepyridine, at room temperature. This intermediate (B) is subjected inSTEP 2 to a Suzuki coupling with reagent (1)((S)-1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan2yl)phenoxy)pyrrolidine)using for example [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl₂), complex with DCM, ascatalyst, in a mixture of dioxane and water and in the presence of abase, for example cesium carbonate (Cs₂CO₃), at room temperature or byheating up to reflux. The preparation of reagent (1) is describedhereunder in SCHEME 2.

The intermediate (C) obtained is brominated in STEP 3 using for examplepyridinium tribromide in DCM or tetrahydrofuran (THF) at roomtemperature. This bromo derivative intermediate (D) is then subjected inSTEP 4 to a second Suzuki coupling with a suitable boronic reagentR6B(OR′)₂, wherein —B(OR′)₂ is a boronic acid or a pinacolate ester andR6 is as above defined, using for example Pd(dppf)Cl₂, complex with DCM,as catalyst, in a mixture of dioxane and water as solvent and in thepresence of a base, for example Cs₂CO₃, at room temperature or byheating up to reflux.

In the above-described reactions, it can be necessary to protectreactive functional groups, for example hydroxy, amino, thio or carboxygroups, where these groups are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups can be used in accordance with standard practice, for example,see T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry”, John Wiley and Sons, 2006.

When R3 or R5 represents a —OH group, this —OH group is protected, forexample as a pivaloyl ester. Deprotection can be performed just afterSTEP 3 or after STEP 4 by treating, with an aqueous solution of sodiumhydroxide 2N (NaOH), a solution of the pivaloyl ester in methanol (MeOH)at room temperature, followed by acidification with an aqueous solutionof hydrogen chloride 2N (HCl).

When R3 represents a —COOH group, this —COOH group is protected, forexample as a methyl ester. Deprotection is performed just after STEP 4by treating, with an aqueous solution of sodium hydroxide (NaOH) 2N, asolution of the methyl ester in MeOH at room temperature, followed byacidification with an aqueous solution of HCl 2N.

In an embodiment, it can be advantageous to use a variation of SCHEME 1,called SCHEME 1a depicted below, that consists in transformingintermediate (D) into a boronate derivative which is engaged in a Suzukicoupling with an halogenated derivative R6-Hal, wherein R6 is as abovedefined and Hal represents a halogen atom selected from a chlorine, abromine or an iodine atom. Deprotection of the —OH group or —COOH groupof R3 or R5 can be performed before or after STEP 1 or STEP 2 of SCHEME1a, as explained above.

STEP 1 of the above SCHEME 1a consists of reacting intermediate (D) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) using forexample Pd(dppf)C₂, complex with DCM, as catalyst, in a mixture ofdioxane and water and in the presence of a base, for example Cs₂CO₃, atabout 80° C. Intermediate (D′) obtained is engaged in STEP 2 of theabove SCHEME 1a in a Suzuki coupling with R6-Hal, wherein R6 and Hal areas above defined, using for example Pd(dppf)Cl₂, complex with DCM, ascatalyst, in a mixture of dioxane and water as solvent and in thepresence of a base, for example Cs₂CO₃, at about 70° C.

In another embodiment, it can be advantageous, when the compounds offormula (I) are such that R3 is a —COOH group, to use a variation ofSCHEME 1, called SCHEME 1b depicted below.

Hereinabove SCHEME 1b describes the synthesis of the compounds of theformula (Ib) wherein R3 represents a —COOH group, by generating the—COOH group from the —OH group of R3 of the compounds of formula (Ia)wherein R1, R2, R4 and R6 are as above defined in formula (I). In STEP 1of SCHEME 1b the —OH group of R3 in the compounds of formula (Ia) istransformed into a triflate group with, for example Tf₂O in DCM with abase, for example pyridine, at room temperature.

The intermediate (K) obtained is then carbonylated in STEP 2 of SCHEME1b under 2 to 10 bars of carbon monoxide (CO) at about 70° C. in amixture of MeOH and N,N-dimethylformamide (DMF) using for examplepalladium acetate (Pd(OAc)₂) and 1,3-bis(diphenylphosphino)propane(P(Ph)₂-(CH₂)₃—P(Ph)₂) as catalytic system.

The methyl ester of formula (Ib) then obtained is deprotected as definedabove, so as to obtain compounds of formula (I) wherein R1, R2, R4 andR6 are as above defined in formula (I) and R3 is a —COOH group.

In another embodiment, it can be advantageous as well, when R3represents a —COOH group, to use a variation of SCHEME 1, called SCHEME1c depicted below. This SCHEME 1c is an alternative process to the aboveSCHEME 1b.

Hereinabove SCHEME 1c describes the synthesis of the intermediates (C′″)as defined above by generating the —COOMe group from the —OH group ofintermediates (C′) wherein R1, R2 and R4 are as above defined in formula(I). In STEP 1 of SCHEME 1c, the —OH group is transformed into atriflate group with, for example, Tf₂O in DCM with a base, for examplepyridine, at room temperature.

The intermediate (C″) then obtained is carbonylated in STEP 2 of SCHEME1c under 2 to 10 bars of CO at about 70° C. in a mixture of MeOH and DMFusing for example Pd(dppf)C₂ or Pd(OAc)₂ and P(Ph)₂-(CH₂)₃—P(Ph)₂ ascatalytic system.

In another embodiment, when R1 and R2 represent simultaneously adeuterium atom and R3 is other than a —COOH group, a process ofsynthesis of compounds of formula (Ic) is described below in SCHEME 1dwhich is a variation of the general SCHEME 1.

According to SCHEME 1d, a substituted enol triflate intermediate (B),obtained in accordance to STEP 1 of SCHEME 1, is subjected in STEP 1 ofSCHEME 1d to a Suzuki coupling with compound (c) (tert-butyl(3S)-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate)using for example Pd(dppf)Cl₂, complex with DCM, as catalyst, in dioxaneand in the presence of a base, for example Cs₂CO₃, at room temperature.

The intermediate (E) then obtained is brominated in STEP 2 of SCHEME 1dusing for example pyridinium tribromide in DCM or THF at roomtemperature.

This bromo derivative intermediate (F) obtained is then subjected inSTEP 3 of SCHEME 1d to a second Suzuki coupling with a suitable boronicreagent R6B(OR′)₂, wherein the —B(OR′)₂ group is a boronic acid or apinacolate ester, and R6 is as above defined, using for examplePd(dppf)Cl₂, complex with DCM, as catalyst, in a mixture of dioxane andwater and in the presence of a base, for example Cs₂CO₃, at roomtemperature or by heating up to reflux.

This intermediate (G) obtained is N-deprotected in STEP 4 of SCHEME 1dusing for example a 4N solution of HCl in dioxane, at room temperature.

The NH-pyrrolidine intermediate (H) obtained is amidified in STEP 5 ofSCHEME 1d using for example 3-fluoropropionic acid in DMF at roomtemperature using for example1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl) as coupling agent.

Finally, the carbonyl of the amide intermediate (J) then obtained isreduced in STEP 6 of SCHEME 1d into the deuteriated amine of formula(Ic) by for example lithium aluminum deuteride (LiAlD₄) in ether (Et₂O)at room temperature.

When R3 or R5 is a —OH group, this —OH group is protected, for exampleas a pivaloyl ester. Deprotection is done at the final STEP 6 forexample by reduction with LiAlD₄.

According to the above SCHEME 2, commercially available compound (a)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol) is condensed inSTEP 1 of SCHEME 2 in THF at room temperature on(R)-1-N-Boc-3-hydroxypyrrolidine usingN,N,N′,N′-tetramethylazodicarboxamide as coupling agent.

Compound (c) thus obtained is N-deprotected in STEP 2 of SCHEME 2 inMeOH at room temperature using an acidic agent for example a solution ofHCl 4N in dioxane.

Alkylation of the pyrrolidine nitrogen is then performed in STEP 3 ofSCHEME 2 by reacting compound (d) with the corresponding1,1-disubstituted 1-halogeno-3-fluoro propane, for example1-iodo-3-fluoropropane in acetonitrile in presence of potassiumcarbonate (K₂CO₃) at about 40° C.

The new intermediate (A10) wherein R3 represents a —COOMe group, R4represents a fluorine atom and R5 represents a hydrogen atom can beprepared according to reaction SCHEME 3 highlighted below:

According to SCHEME 3, intermediate (A6) (1-fluoro 2-methoxy5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene) is converted in STEP 1into the corresponding phenol intermediate (A7) by treatment for examplewith aluminum trichloride (AlCl₃) in toluene at about 90° C.

The —OH group is then transformed in STEP 2 of SCHEME 3 into a triflategroup by treatment with a base, for example 2,6-dimethyl-pyridine(lutidine), using for example Tf₂O in DCM at room temperature to obtainintermediate (A9).

The intermediate (A9) then obtained is finally carbonylated in STEP 3 ofSCHEME 3 in the presence of a base, for example triethylamine (Et₃N) anda catalyst, for example Pd(OAc)₂, under 2 to 10 bars of CO in a mixtureof DMF and MeOH at about 70° C. to produce intermediate (A10) (1-fluoro5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene 2-carboxylic acid, methylester).

In the above SCHEMES 1, 1a, 1b, 1c, 1d, 2 and 3 the starting compoundsand the reactants, when their preparation is not herein described, arecommercially available, for example by Sigma-Aldrich, Fluka, AcrosOrganics, Alfa Aesar, and the like, or are described in the literature,or may be prepared by methods which are known to a person skilled in theart.

In another aspect, provided are the compounds as defined below, whereinR1, R2, R3, R4, R5 and R6 are as defined in formula (I) above, which areuseful as intermediates or reagents in the synthesis of the compounds ofthe formula (I) as above defined, or salts thereof:

Some compounds of formula (I) are described, with their structure, name,method of preparation and analytical data, in the below Table 1, whichis merely illustrative and does not limit the scope of the presentinvention.

The methods of preparation A, B and C mentioned in table 1 arerespectively described in examples 1, 51 and 48 below.

The examples with numbers underlined in Table 1 are further detailedhereafter.

The 1H NMR spectra at 400 and 500 MHz were performed on a Bruker AvanceDRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with thechemical shifts (5 in ppm) in the solvent dimethyl sulfoxide-d6(d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Couplingconstants (J) are given in Hertz.

The liquid chromatography/mass spectra (LC/MS) were obtained on a UPLCAcquity Waters instrument, light scattering detector Sedere and SQDWaters mass spectrometer using UV detection DAD 210<I<400 nm and columnAcquity UPLC CSH C18 1.7 μm, dimension 2.1×30 mm, mobile phase H₂O+0.1%HCO₂H/CH₃CN+0.1% HCO₂H.

TABLE 1 MASS: LC/MS Exam- (m/z, ples Structure Name Method NMR MH+): 1

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-hydroxyphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-3-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 1.98(m, 2 H); 2.20 (m, 3 H); 2.39 (m, 1 H); 2.48 (m, 2 H); 2.54 (m, 1 H);2.63 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4,48 (td, J = 6.1and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.19 (d, J = 2.6 Hz, 1 H); 6.55 (m, 3H); 6.62 (d, J = 8.82 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.92 (d, J =8.6 Hz, 2 H); 7.04 (d, J = 8.6 Hz, 474 1 H); 8.98 (s, 1 H); 9.28 (s, 1H) 2

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(3-hydroxyphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-3-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 1.99(m, 2 H); 2.19 (m, 3 H); 2.35 to 2.68 (m, 7 H); 2.80 (m, 1 H); 4.47 (td,J = 6.0 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.20 (d, J = 2.5 Hz, 1 H);6.48 to 6.55 (m, 3 H); 6.58 (dd, J = 2.5 and 8.6 Hz, 1 H); 6.62 (d, J =8.6 Hz, 2 H); 6.74 (d, J = 8.6 Hz, 2 H); 6.96 (t, J = 8.2 Hz, 1 H); 7.06(d, J = 8.2 Hz, 1 H); 9.00 474 (s, 1 H); 9.19 (s, 1 H) 3

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1H-indol-5-yl)- 8,9- dihydro- 7H- benzo[7] annulen-3-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.00 (m, 2H); 2.17 (m, 1 H); 2.30 (t, J = 7.0 Hz, 2 H); 2.37 (m, 1 H); 2.44 (t, J= 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.61 (m, 1 H); 2.69 (m, 2 H); 2.78 (dd, =6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1H); 6.21 (d, J = 2.9 Hz, 1 H); 6.29 (t, J = 2.9 Hz, 1 H); 6.58 (m, 3 H);6.74 (d, J = 8.8 Hz, 2 H); 6.85 497 (dd, J = 1.7 and 8.5 Hz, 1 H); 7.07(d, J = 8.3 Hz, 1 H); 7.16 (d, J = 8.5 Hz, 1 H); 7.25 (t, J = 2.9 Hz, 1H); 7.34 (s, 1 H); 8.99 (s, 1 H); 10.97 (m, 1 H) 4

6-(2- chloro-4- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-3-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.03 (m, 2 H); 2.15 (t, J = 7.0 Hz, 2 H); 2.20 (m, 1 H); 2.38 (m,1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.52 (dd, J = 3.2 and 10.4 H z, 1 H);2.62 (m, 1 H); 2.69 to 2.82 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2H); 4.72 (m, 1 H); 6.20 (d, J = 2.7 Hz, 1 H); 6.62 (dd, J = 2.7 and 8.3Hz, 1 H); 6.64 (d, J = 8.8 Hz, 2 H); 6.72 510 (d, J = 8.8 H z, 2 H);7.04 (dt, J = 2.7 and 9.0 Hz, 1 H); 7.10 (d, J = 8.3 Hz, 1 H); 7.17 (dd,J = 6.4 and 8.9 Hz, 1 H); 7.40 (dd J = 2.7 and 8.9 Hz, 1 H); 9.07 (s, 1H) 5

6-(2- chloro-4- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.08 (m, 2 H); 2.19 (m, 3 H); 2.37 (m, 1 H); 2.46 (t, J = 7.2 Hz,2 H); 2.53 (m, 1 H); 2.61 to 2.83 (m, 4 H); 4.47 (td, J = 6.2 and 47.6Hz, 2 H); 4.72 (m, 1 H); 6.57 (s, 2 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.71(m, 3 H); 7.02 (dt, J = 2.6 and 9.0 Hz, 1 H); 7.17 (dd, J = 6.4 and 9.0Hz, 1 H); 7.39 (dd, J = 2.6 and 9.0 Hz, 1 H); 9.43 508 (s, 1 H) 6

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(3-hydroxy- phenyl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.03(m, 2 H); 2.20 (m, 3 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.55(dd, J = 3.2 and 10.4 Hz, 1 H); 2.66 (m, 3 H); 2.80 (dd, J = 6.3 and10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.48to 6.55 (m, 5 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J =8.8 Hz, 2 H); 6.94 (t, J = 8.0 Hz, 1 474 H); 9.15 (s, 1 H); 9.39 (s, 1H) 7

6-(3- chloro-2- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6), δ ppm): 1.66 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.01 to 2.23 (m, 5 H); 2.20 (s, 3 H); 2.35 (m, 1 H); 2.45 (t, J =7.2 Hz, 2 H); 2.52 (m, 1 H); 2.60 to 2.82 (m, 4 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.57 (d, J = 1.5 Hz, 2 H); 6.59 (d, J= 8.9 Hz, 2 H); 6.66 (d, J = 8.9 Hz, 2 H); 6.71 (t, J = 1.5 Hz, 1 H);6.97 (d, J = 8.0 Hz, 1 H); 7.03 (t, J = 8.0 Hz, 1 506 H); 7.21 (d, J =8.0 Hz, 1 H); 9.41 (s, 1 H) 8

6-(2- chloro-3- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.08 (m, 2 H); 2.18 (m, 3 H); 2.37 (m, 1 H); 2.43 (t, J = 7.2 Hz,2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.78 (m, 3 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.71 (m, 1 H); 6.58 (s, 2 H); 6.60 (d, J = 8.9 Hz, 2 H);6.70 (s, 1 H); 6.72 (d, J = 8.9 Hz, 2 H); 6.99 (m, 1 H); 7.20 (m, 2 H);9.46 (s, 1 H) 510 9

6-(2-fluoro- 4-methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.03 (m, 2 H); 2.12 to 2.22 (m, 3 H); 2.23 (s, 3 H); 2.38 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.63 (m, 1 H); 2.49 (t, J= 7.2 Hz, 2 H); 2.79 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.47 (td, J = 6.3and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.56 (s, 2 H); 6.59 (d, J = 8.8 Hz, 2H); 6.69 (s, 1 H); 6.71 (d, J = 8.8 Hz, 2 H); 490 6.82 (d, J = 8.0 Hz, 1H); 6.87 (d, J = 11.3 Hz, 1 H); 7.00 (t, J = 8.0 Hz, 1 H); 9.41 (s, 1 H)10

6-(2-fluoro- 4-hydroxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.04 (m, 2 H); 2.13 (t, J = 7.0 Hz, 2 H); 2.20 (m, 1 H); 2.38 (m,1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H);2.60 to 2.70 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J= 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.40 (dd, J = 2.6 and 11.9 Hz,1H); 6.42 (dd, 492 J = 2.6 and 8.7 Hz, 1H); 6.4 (m, 2 H); 6.60 (d, J =8.8 Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.89 (t, J = 8.7Hz, 1 H); 9.39 (s, 1 H); 9.70 (s, 1 H) 11

5-[4-[(3S)- 1-(3- floropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-hydroxyphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.02(m, 2 H); 2.20 (m, 3 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.54(dd, J = 3.2 and 10.4 H z, 1 H); 2.63 (m, 3 H); 2.80 (dd, J = 6.4 and10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.52(m, 4 H); 6.60 (d, J = 8.8 H z, 2 H); 6.68 (s, 1 H); 6.71 (d, J = 8.8Hz, 2 H); 6.91 (d, J = 8.8 Hz, 2 474 H); 9.23 (s, 1 H); 9.32 (s, 1 H) 12

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1H-indol-5-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.03 (m, 2H); 2.15 (m, 1 H); 2.30 (t, J = 7.0 Hz, 2 H); 2.37 (m, 1 H); 2.45 (t, J= 7.2 Hz, 2 H); 2.51 (m, 1 H); 2.61 (m, 1 H); 2.70 (t, J = 7.0 Hz, 2 H);2.77 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2H); 4.69 (m, 1 H); 6.28 (t, J = 2.8 Hz, 1 H); 6.53 (d, J = 8.8 Hz, 2 H);6.55 (m, 2 H); 6.68 (d, J = 1.5 Hz, 497 1 H); 6.73 (d, J = 8.8 Hz, 2 H);6.84 (dd, J = 1.8 and 8.5 Hz, 1 H); 7.13 (d, J = 8.5 Hz, 1 H); 7.23 (t,J = 2.8 Hz, 1 H); 7.32 (d, J = 1.8 Hz, 1 H); 9.38 (s, 1 H); 11.90 (t, J= 2.8 Hz, 1 H) 13

6-(4- chloro-3- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.00 to 2.23 (m, 4 H); 2.12 (s, 3 H); 2.38 (m, 1 H); 2.46 (t, J =7.2 Hz, 2 H); 2.53 (m, 1 H); 2.59 to 2.81 (m, 5 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.56 (s, 2 H); 6.59 (d, J = 8.8 Hz, 2H); 6.65 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 7.01 (d, J = 8.5 Hz, 1 H);7.09 (dd, J = 2.4 and 8.5 Hz, 1 H); 7.18 506 (d, = 2.4 Hz, 1 H); 9.39(s, 1 H) 14

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(3-fluoro-4- pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H);2.05 (m, 2 H); 2.20 (m, 3 H); 2.38 (m, 1 H); 2.45 (t, J = 7.3 Hz, 2 H);2.53 (m, 1 H); 2.60 to 2.71 (m, 3 H); 2.79 (dd, J = 6.1 and 10.4 Hz, 1H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.59 (m, 2 H);6.63 (d, J = 8.9 Hz, 2 H); 6.73 (m, 3 H); 7.25 (dd, J = 5.0 and 6.4 Hz,1 H); 8.24 (dd, J = 1.7 477 and 5.0 Hz, 1 H); 8.37 (d, J = 1.7 Hz, 1 H);9.50 (s, 1 H) 15

6-(4- chloro-2- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.06 (m, 2 H); 2.13 to 2.24 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.53 (m, 1 H); 2.73 (m, 1 H); 2.70 (t, J = 7.2 Hz, 2 H);2.80 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.47 (td, J = 6.3 and 47.5 Hz, 2H); 4.73 (m, 1 H); 6.58 (s, 2 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1H); 6.72 (d, J = 8.8 Hz, 2 H); 7.11 (dd, J = 2.2 510 and 8.2 Hz, 1 H);7.18 (t, J = 8.2 Hz, 1 H); 7.27 (dd, J = 2.2 and 9.9 Hz, 1 H); 9.41 (s,1 H) 16

6-(4- chloro-3- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.06 (m, 2 H); 2.15 to 2.19 (m, 3 H); 2.39 (m, 1 H); 2.48 (m, 2H); 2.55 (m, 1 H); 2.68 (m, 3 H); 2.80 (dd, J = 6.3 and 10.4 Hz, 1 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1 H); 6.57 (s, 2 H); 6.67(d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.75 (d, J = 8.8 Hz, 2 H); 6.94(dd, J = 2.0 and 8.6 Hz, 1 H); 7.13 (dd, 510 J = 2.0 and 11.0 Hz, 1 H);7.34 (t, J = 8.5 Hz, 1 H); 9.42 (s, 1 H) 17

6-(4-fluoro- 2-methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.02 to 2.24 (m, 5 H); 2.12 (s, 3 H); 2.38 (m, 1 H); 2.45 (t, J =7.2 Hz, 2 H); 2.52 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.59 to 2.82 (m, 4H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.55 (s, 2 H);6.58 (d, J = 8.8 Hz, 2 H); 6.67 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H);6.74 (dt, J = 3.1 and 8.9 Hz, 1 H); 6.93 (dd, 490 J = 3.1 and 10.4 Hz, 1H); 7.02 (dd, J = 6.6 and 8.9 Hz, 1 H); 9.34 (s, 1 H) 18

6-(2,4- dichloro- phenyl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.06(m, 2 H); 2.18 (m, 3 H); 2.38 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.53(m, 1 H); 2.62 (m, 1 H); 2.69 to 2.82 (m, 3 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.72 (m, 1 H); 6.57 (s, 2 H); 6.61 (d, J = 8.8 Hz, 2 H);6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 7.14 (d, J = 8.8 Hz, 1 H);7.23 (dd, J = 2.5 and 8.8 Hz, 1 H); 7.54 526 (d, J = 2.5 Hz, 1 H); 9.42(s, 1 H) 19

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1H-indol-6-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.03 (m, 2H); 2.15 (m, 1 H); 2.25 to 2.40 (m, 3 H); 2.43 (t, J = 7.2 Hz, 2 H);2.52 (m, 1 H); 2.61 (m, 1 H); 2.69 (t, J = 7.0 Hz, 2 H); 2.77 (dd, J =6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1H); 6.30 (t, J = 2.8 Hz, 1 H); 6.53 (d, J = 8.8 Hz, 2 H); 6.55 (s, 2 H);6.70 (s, 1 H); 6.73 (d, J = 8.8 497 Hz, 2 H); 6.79 (dd, J = 1.6 and 8.3Hz, 1 H); 7.15 (s, 1 H); 7.24 (t, J = 2.8 Hz, 1 H); 7.31 (d, J = 8.3 Hz,1 H); 9.35 (s, 1 H); 10.89 (t, J = 2.8 Hz, 1 H) 20

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1H-indol-4-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.62 (m, 1 H); 1.77 (dm, J = 25.3 Hz, 2 H); 2.00 (m, 2H); 2.13 (m, 1 H); 2.31 (m, 3 H); 2.41 (t, J = 7.2 Hz, 2 H); 2.57 (m, 2H); 2.74 (m, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.65 (m, 1 H);6.25 (d, J = 3.0 Hz, 1 H); 6.44 (d, J = 8.8 Hz, 2 H); 6.58 (s, 2 H);6.72 (m, 3 H); 6.71 (s, 1 H); 6.89 (t, J = 8.3 Hz, 1 H); 7.15 (d, J =8.3 Hz, 1 H); 7.22 (7, J = 3.0 Hz, 497 1 H); 9.38 (s, 1 H); 11.00 (m, 1H) 21

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-indolin-5- yl-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.01 (m, 2H); 2.19 (m, 3 H); 2.39 (m, 1 H); 2.42 to 2.57 (m, 3 H); 2.61 (m, 3 H);2.82 to 2.92 (m, 3 H); 3.38 (m, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2H); 4.75 (m, 1 H); 5.39 (s, 1 H); 6.24 (d, J = 8.0 Hz, 1 H); 6.51 (s, 2H); 6.60 (d, J = 8.8 Hz, 2 H); 6.64 (m, 2 H); 6.72 (d, J = 8.8 Hz, 2 H);6.81 (s, 1 H); 9.30 (s, 499 1 H) 22

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1H-pyrrolo[2,3- b]pyridin- 5-yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.17 (m, 1 H); 2.29 to 2.40 (m, 3 H): 2.44 (t, J =7.2 Hz, 2 H); 2.52 (m, 1 H); 2.61 (m, 1 H); 2.71 (t, J = 7.0 Hz, 2 H);2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2H); 4.71 (m, 1 H); 6.32 (dd, J = 2.0 and 2.9 Hz, 1 H); 6.57 (s, 2 H);6.59 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.74 498 (d, J = 8.8 Hz, 2 H);7.38 (t, J = 2.9 Hz, 1 H); 7.77 (d, J = 2.9 Hz, 1 H); 7.89 (d, J = 2.9Hz, 1 H); 9.39 (s, 1 H); 11.49 (t, J = 2.9 Hz, 1 H) 23

6-(2- chloro-4- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.05 (m, 2 H); 2.11 to 2.22 (m, 3 H); 2.23 (s, 3 H); 2.38 (m, 1H); 2.45 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.58 to 2.83 (m, 4 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.56 (s, 2 H); 6.58(d, J = 8.8 Hz, 2 H); 6.72 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.92 (d,J = 8.3 Hz, 1 H); 6.99 (d, J = 8.3 Hz, 1 H); 7.21 (s, 1 H); 506 9.41 (s,1 H) 24

tert-butyl 4-[5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 2- hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6-yl]-3,6- dihydro- 2H- pyridine-1- A 1H NMR (400 MHz, DMSO-d, δ ppm):1.38 (s, 9 H); 1.70 to 2.08 (m, 9 H); 2.24 (m, 1 H); 2.40 (m, 1 H); 2.45to 2.57 (m, 4 H); 2.60 (dd, J = 3.01 and 10.4 Hz, 1 H); 2.67 (m, 1 H);2.83 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.24 (m, 2 H); 3.71 (m, 2 H); 4.49(td, J = 6.1 and 47.5 Hz, 2 H); 4.80 (m, 1 H); 5.48 (m, 1 H); 6.52 (m, 2H); 6.64 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 6.91 (d, J = 8.8 Hz, 2 H);563 carboxylate 9.34 (s, 1 H) 25

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1-methyl- 3,6- dihydro- 2H-pyridin- 4-yl)-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 to 1.89 (m, 3 H);1.93 to 2.08 (m, 6 H); 2.14 (s, 3 H); 2.20 to 2.32 (m, 3 H); 2.40 (m, 1H); 2.46 to 2.55 (m, 4 H); 2.60 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.69 (m,1 H); 2.75 (m, 2 H); 2.84 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.49 (td, J =6.1 and 47.5 Hz, 2 H); 4.81 (m, 1 H); 5.42 (m, 1 H); 6.51 (s, 2 H); 6.63(s, 1 H); 6.73 (d, J = 8.8 Hz, 2 H); 6.91 (d, J = 8.8 Hz, 477 2 H); 9.31(s, 1 H) 26

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1,2,3,6- tetrahydro pyridin-4- yl)-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 to 1.89 (m, 5 H);1.93 to 2.08 (m, 4 H); 2.15 (m, 1 H); 2.25 (m, 1 H); 2.40 (m, 1 H); 2.45to 2.55 (m, 4 H); 2.60 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H);2.83 (dd, J = 6.3 and 10.4 Hz, 1 H); 3.11 (m, 2 H); 4.48 (td, J = 6.1and 47.5 Hz, 2 H); 4.81 (m, 1 H); 5.44 (m, 1 H); 6.51 (s, 2 H); 6.53 (s,1 H); 6.73 (d, J = 8.8 Hz, 2 H); 6.92 (d, J = 8.8 Hz, 434 2 H); 9.31 (s,1 H) 27

6-(4- ethoxy-2- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.29 (t, J = 7.1 Hz, 3 H); 1.68 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 1.99 to 2.23 (m, 5 H); 2.08 (s, 3 H);2.35 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.59 to 2,81(m, 4 H); 3.94 (q, J = 7.1 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2H); 4.70 (m, 1 H); 6.55 (m, 4 H); 6.59 (dd, J = 2.5 and 8.7 Hz, 1 H);6.66 (m, 3 H); 6.70 (s, 1 H); 6.90 (d, J = 8.7 Hz, 1 516 H); 9.36 (s, 1H) 28

6- (benzofuran- 5-yl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.05(m, 2 H); 2.19 (m, 1 H); 2.20 (t, J = 7.0 Hz, 2 H); 2.35 to 2.80 (m, 6H); 2.70 (t, J = 7.0 Hz, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73(m, 1 H); 6.58 (m, 4 H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.82(dd, J = 1.1 and 2.5 Hz, 1 H); 7.05 (d, J = 2.0 and 8.7 Hz, 1 H); 7.37(d, J = 8.7 Hz, 1 H); 7.42 (d, J = 2.0 498 Hz, 1 H); 7.91 (d, J = 2.5Hz, 1 H); 9.39 (s, 1 H) 29

6-(2-fluoro- 4- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.03 (m, 2 H); 2.15 (t, J = 7.0 Hz, 2 H); 2.20 (m, 1 H); 2.39 (m,1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.60 to 2.71 (m, 3 H);2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.71 (s, 3 H); 4.48 (td, J = 6.1and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.55 (s, 2 H); 6.60 (m, 3 H); 6.65 to6.73 (m, 4 H); 7.02 (t, J = 8.9 Hz, 1 H); 9.40 506 (s, 1 H) 30

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2-methyl-1H- indol-5-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.61 to 1.87 (m, 3 H); 2.02 (m, 2 H); 2.15(m, 1 H); 2.22 to 2.80 (m, 13 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H);4.70 (m, 1 H); 5.95 (s, 1 H); 6.52 (m, 4 H); 6.65 to 6.79 (m, 4 H); 7.02(d, J = 8.5 Hz, 1 H); 7.16 (s, 1 H); 9.31 (s, 1 H); 10.76 (m, 1 H) 51131

6-(2,3- dimethyl- phenyl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 1.98to 2.22 (m, 5 H); 2.10 (s, 3 H); 2.19 (s, 3 H); 2.36 (m, 1 H); 2.45 (t,J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.59 to 2.70 (m, 2 H); 2.72 (m, 2 H);4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.54 (d, J = 8.8 Hz,2 H); 6.57 (s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.79 (d,J = 7.8 Hz, 1 H); 6.77 (t, J = 7.8 Hz, 1 486 H); 6.92 (d, J = 7.9 Hz, 1H); 9.38 (s, 1 H) 32

6-(4- chloro-2- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.00 to 2.24 (m, 5 H); 2.13 (s, 3 H); 2.36 (m, 1 H); 2.45 (t, J =7.2 Hz, 2 H); 2.52 (m, 1 H); 2.59 to 2.81 (m, 4 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.55 (s, 2 H); 6.58 (d, J = 8.8 Hz, 2H); 6.65 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 7.02 (d, J = 8.2 Hz, 1 H);7.10 (d, J = 8.2 Hz, 1 H); 7.19 (s, 1 H); 506 9.40 (s, 1 H) 33

6-(3-fluoro- 2-methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.00 to 2.23 (m, 5 H); 2.03 (s, 3 H); 2.36 (m, 1 H); 2.44 (t, J =7.2 Hz, 2 H); 2.53 (m, 1 H); 2.59 to 2.80 (m, 4 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.55 (s, 2 H); 6.58 (d, J = 8.8 Hz, 2H); 6.65 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 6.88 (d, J = 7.8 Hz, 1 H);6.92 (m, 1 H); 7.16 (m, 1 H); 9.41 (s, 1 H) 490 34

6-(6- ethoxy-3- pyridyl-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.26 (t, J = 7.1 Hz, 3 H); 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.15 to 2.28 (m, 3 H); 2.38 (m, 1H); 2.47 (t, J = 7.1 Hz, 2 H); 2.55 (m, 1 H); 2.66 (m, 3 H); 2.80 (dd, J= 6.5 and 10.5 Hz, 1 H); 4.20 (q, J = 7.1 Hz, 2 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.76 (m, 1 H); 6.55 (s, 2 H); 6.60 (d, J = 8.7 Hz, 1H); 6.64 (d, J = 8.8 Hz, 2 H); 503 6.69 (s, 1 H); 6.76 (d, J = 8.8 Hz, 2H); 7.43 (dd, J = 2.4 and 8.7 Hz, 1 H); 7.84 (d,J = 2.4 Hz, 1 H); 9.40(s, 1 H) 35

6-(3-fluoro- 4-methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.02 (m, 2 H); 2.13 (s, 3 H); 2.17 to 2.27 (m, 3 H); 2.39 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.66(m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.76 (m, 1 H); 6.54 (s, 2 H); 6.62 (d, J = 8.8 Hz, 2 H);6.69 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 490 6.84 (m, 2 H); 7.04 (t, J= 8.2 Hz, 1 H); 9.41 (s, 1 H) 36

5-[4-[(3S)- 1-(1,1- dideuterio- 3-fluoro- propyl) pyrrolidin-3-yl]oxyphenyl]- 6-(2- fluoro-4- methylphenyl)- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.77(td, J = 6.3 and 25.6 Hz, 2 H): 2.04 (m, 2 H); 2.12 to 2.23 (m, 3 H);2.24 (s, 3 H); 2.38 (m, 1 H); 2.53 (m, 1 H); 2.63 (m, 1 H); 2.70 (t, J =7.0 Hz, 2 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 4,47 (td, J = 6.3 and47.7 Hz, 2 H); 4.72 (m, 1 H); 6.56 (s, 2 H); 6.59 (d, J = 8.8 Hz, 2 H);6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.82 (d, J = 8.1 Hz, 1 H);6.88 (d, J = 11.6 Hz, 1 H); 7.00 (t, J = 8.1 Hz, 492 1 H); 9.42 (s, 1 H)37

6-(3- chloro-4- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2,03 (m, 2 H); 2.15 to 2.28 (m, 3 H); 2.21 (s, 3 H); 2.39 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.2 and 10.5 Hz, 1 H); 2.65(m, 3 H); 2.79 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.76 (m, 1 H); 6.56 (s, 2 H); 6.64 (d, J = 9.0 Hz, 2 H);6.70 (s, 1 H); 6.74 (d, J = 9.0 Hz, 2 H); 506 6.98 (dd, J = 1.9 and 8.0Hz, 1 H); 7.10 (d, J = 1.9 Hz, 1 H); 7.12 (d, J = 8.0 Hz, 1 H); 9.41 (s,1 H) 38

6-(3,4- dichloro- phenyl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.4 Hz, 2 H); 2.05(m, 2 H); 2.20 (m, 1 H); 2.26 (t, J = 7.2 Hz, 2 H); 2.39 (m, 1 H); 2.47(t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.5 Hz, 1 H); 2.67 (m, 3H); 2.80 (dd, J = 6.4 and 10.5 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz,2 H); 4.78 (m, 1 H); 6.57 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 s, 1H); 6.76 (d, J = 8.8 Hz, 2 H); 526 7.09 (dd, J = 2.2 and 8.5 Hz, 1 H);7.32 (d, J = 2.2 Hz, 1 H); 7.40 (d, J = 8.5 Hz, 1 H); 9.47 (s, 1 H) 39

6-(3- chloro-2- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.19 (m, 3 H); 2.38 to 2.58 (m, 4 H); 2.60 to 2.81(m, 4 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.56 (s, 2H); 6.61 (d, J = 8.8 Hz, 2 H); 6.71 (m, 3 H); 7.05 (t, J = 8.2 Hz, 1 H);7.13 (m, 1 H); 7.36 (m, 1 H); 9.48 (s, 1 H) 510 40

6-(4-fluoro- 2- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 1.95 to 2.23 (m, 5 H); 2.31 to 2.55 (m, 4 H); 2.60 to 2.72 (m, 3H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.72 (s, 3 H); 4.45 (td, J =6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.48 to 6.61 (m, 5 H); 6.71 (m, 3H); 6.83 (m, 2 H); 9.37 (s, 1 H) 506 41

6-(3-fluoro- 2- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): (dm, J = 25.3 Hz, 2 H); 2.04 (m, 2 H);2.13 to 2.24 (m, 3 H); 2.37 (m, 1 H); 2.44 (t, J = 7.2 Hz, 2 H); 2.52(m, 1 H); 2.62 (m, 1 H); 2.71 (t, J = 7.0 Hz, 2 H); 2.78 (dd, J = 6.4and 10.4 Hz, 1 H); 3.74 (s, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H);4.72 (m, 1 H); 6.57 (m, 2 H); 6.59 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H);6.73 (d, J = 8.8 Hz, 2 H); 6.78 (dd, J = 2.0 and 506 8.2 Hz, 1 H); 6.85(td, J = 5.0 and 8.2 Hz, 1 H); 7.03 (ddd, J = 2.0 and 8.2 and 12.2 Hz, 1H); 9.40 (s, 1 H) 42

6-(4- ethoxy-2- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.38 (t, J = 7.1 Hz, 3 H); 1.68 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.04 (m, 2 H); 2.10 to 2.24 (m, 3 H);2.38 (m, 1 H); 2.42 to 2.58 (m, 3 H); 2.59 to 2.71 (m, 3 H); 2.79 (m, 1H); 6.98 (q, J = 7.1 Hz, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72(m, 1 H); 6.62 to 6.76 (m, 9 H); 7.00 (t, J = 8.8 Hz, 1 H); 9.40 (s, 1H) 520 43

6-(2- chloro-4- ethoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.26 (t, J = 7.3 Hz, 3 H); 1.66 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.02 to 2.25 (m, 5 H); 2.35 (m, 1 H);2.46 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.59 to 2.82 (m, 4 H); 3.98(q, J = 7.3 Hz, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1H); 6.54 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 (m, 4 H); 6.93 (d, J= 2.4 Hz, 1 H); 6.99 (d, J = 8.9 Hz, 1 H); 536 9.41 (s, 1 H) 44

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-methoxy- 2-methyl- phenyl)- 8,9- dihydro- 7H benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2H); 1.98 to 2.22 (m, 5 H); 2.08 (s, 3 H); 2.36 (m, 1 H); 2.43 (m, 2 H);2.53 (m, 1 H); 2.59 to 2.82 (m, 4 H); 3.68 (s, 3 H); 4.46 (td, J = 6.1and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.50 to 6.71 (m, 9 H); 6.91 (d, J =8.3 Hz, 1 H); 9.36 (s, 1 H) 502 45

1-fluoro-6- (2-fluoro-4- methyl- phenyl)-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.19 (m, 3 H); 2,22 (s, 3 H);2,38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.63 (m, 1 H);2.79 (m, 3 H); 4.47 (td, J = 6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.40(d, J = 8.5 Hz, 1 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.73 d, J = 8.8 Hz, 2H); 6.74 (t, J = 8.5 Hz, 1 H); 6.83 (d, J = 8.0 Hz, 1 H); 6.89 (d, J =11.2 Hz, 1 H); 7.01 (t, J = 8.0 Hz, 1 H); 9.83 508 (s, 1 H) 46

6-(4- ethoxy-2- methyl- phenyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (t, J = 7.1 Hz, 3H); 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.00 to 2.23 (m, 5 H);2.10 (s, 3 H); 2.37 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H);2.62 (m, 1 H); 2.74 to 2.85 (m, 3 H); 3.93 (q, J = 7.1 Hz, 2 H); 4.47(td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.49 (d, J = 9.0 Hz, 1H); 6.56 (d, J = 8.9 Hz, 2 H); 6.59 (dd, J = 2.6 and 8.6 Hz, 1 H); 6.65(d, J = 2.6 Hz, 1 H); 534 6.68 (d, J = 8.6 Hz, 2 H); 6.71 (t, J = 9.0Hz, 1 H); 6.90 (d, J = 8.6 Hz, 1 H); 9.80 (s, 1 H) 47

6-(2,4- dichloro- phenyl)-1- fluoro-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.06 (m, 2 H); 2.19 (m, 3 H); 2.38 (m, 1 H); 2.48 (t, J = 7.2 Hz,2 H); 2.53 (m, 1 H); 2.64 (m, 1 H); 2.70 to 2.83 (m, 2 H); 2.98 (m, 1H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.40 (d, J = 8.6Hz, 1 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.73 (m, 3 H); 7.17 (d, J = 8.6 Hz,1 H); 7.25 (dd, J = 1.5 and 8.6 Hz, 1 H); 7.58 (d, J = 1.5 544 Hz, 1 H);9.89 (s, 1 H) 48

6-(2-fluoro- 4-methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2-carboxylic acid C 1H NMR (400 MHz, DMSO-d6), δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.07 to 2.22 (m, 5 H); 2.25 (s, 3 H); 2.37 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.64 (m, 1 H); 2.89 (dd, J= 6.3 and 10.5 Hz, 1 H); 2.83 (t, J = 6.8 Hz, 2 H); 4.46 (td, J = 6.1and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.62 (d, J = 8.9 Hz, 2 H); 6.72 (d, J= 8.9 Hz, 2 H); 4.73 (m, 1 H); 6.62 (d, J = 8.9 Hz, 2 H); 6.72 (d, J =8.9 Hz, 2 518 H); 6.80 to 6.89 (m, 2 H); 6.91 (dd, J = 1.7 and 11.4 Hz,1 H); 7.05 (t, J = 7.8 Hz, 1 H); 7.72 (dd, J = 1.9 and 8.4 Hz, 1 H);7.89 (d, J = 1.9 Hz, 1 H); 12.90 (m, 1 H) 49

6-(2,3- dihydro- 1,4- benzodioxin- 6-yl)-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.02 (m, 2 H); 2.20 (m, 3 H); 2.39 (m, 1 H);2.47 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64 (m,3 H); 2.80 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.15 (s, 4 H); 4.48 (td, J =6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.50 to 6.65 (m, 7 H); 6.67 (s, 1H); 6.74 (d, J = 8.8 Hz, 2 H); 9.37 (s, 1 H) 516 50

6-(4-fluoro- 3- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.05 (m, 2 H); 2.20 (m, 1 H); 2.28 (t, J = 7.0 Hz, 2 H); 2.39 (m,1 H); 2.45 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H);2.61 to 2.70 (m, 3 H); 2.80 (dd, J = 6.3 and 10.4 Hz, 1 H); 3.59 (s, 3H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.57 (m, 2 H);6.64 (d, J = 8.8 Hz, 2 H): 6.68 (m, 1 H); 6.70 506 (d, J = 2.4 Hz, 1 H);6.75 (d, J = 8.8 Hz, 2 H); 6.83 (dd, J = 2.4 and 8.7 Hz, 1 H); 6.98 (dd,J = 8.7 and 11.8 Hz, 1 H); 9.39 (s, 1 H) 51

6-(2,4- dichloro- phenyl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2- carboxylic acid B1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.07 to 2.23 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H);2.52 (m, 1 H); 2.62 (m, 1 H); 2.55 to 2.89 (m, 3 H); 4.47 (td, J = 6.2and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.63 (d, J = 8.9 Hz, 2 H); 6.71 (m, 3H); 7.18 (d, J = 8.4 Hz, 1 H); 8.26 (dd, J = 2.0 and 8.4 Hz, 1 H); 7.58(d, J = 2.0 Hz, 1 H); 7.63 (d, J = 8.4 Hz, 1 H); 7.79 (s, 1 H); 12.3 (m,1 H) 554 52

6-(4- ethoxy- 2,3- difluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6), δ ppm): 1.31 (t, J = 7.1 Hz, 3 H); 1.69 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.18 (t, J = 7.0 Hz, 2H); 2.20 (m, 1 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J= 3.0 and 10.4 Hz, 1 H); 2.60 to 2.71 (m, 3 H); 2.79 (dd, J = 6.3 and10.4 Hz, 1 H); 4.09 (q, J = 7.1 Hz, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz,2 H); 4.73 (m, 1 H); 6.57 (s, 2 H); 6.62 (d, 538 J = 8.8 Hz, 2 H); 6.70(s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6,80 to 6.91 (m, 2 H); 9.41 (s, 1H) 53

6-(4- chloro-3- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2-carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.10 (m, 2 H); 2.17 to 2.28 (m, 3 H); 2.39 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.2 and 10.5 Hz, 1 H); 2.66(m, 1 H); 2.80 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1H); 6.68 (d, J = 8.9 Hz, 2 H); 6.73 (m, 1 H); 6.76 (d, J = 8.9 Hz, 2 H);6.99 (dd, J = 2.3 and 8.4 Hz, 1 H); 7.20 (dd, J = 2.3 and 10.8 Hz, 1 H);7.39 (t, J = 8.4 Hz, 1 H); 538 7.66 (d, J = 8.5 Hz, 1 H); 7.80 (s, 1 H);12.90 (m, 1 H) 54

6-(1,3- benzoxazol- 5-yl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.05(m, 2 H); 2.17 (m, 1 H); 2.30 to 2.39 (m, 3 H); 2.44 (t, J = 7.2 Hz, 2H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.70 (t, J = 7.0 Hz, 2 H); 2.77 (dd, J= 6.2 and 10.5 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1H); 6.55 (m, 4 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 7.19 (dd, J= 1.6 and 8.8 Hz, 1 H); 7.54 499 (m, 2 H); 8.65 (s, 1 H); 9.39 (s, 1 H)55

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 3-yl]oxyphenyl]- 6-(4- hydroxyphenyl)- 8,9- dihydro- 7H- benzo[7]annulene-2- carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m,1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.08 (m, 2 H); 2.20 (m, 3 H); 2.38(m, 1 H); 2.47 (m, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64 (m, 1H); 2.73 to 2.83 (m, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m,1 H); 6.56 (d, J = 8.8 Hz, 2 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.73 (d, J =8.8 Hz, 2 H); 6.77 (d, J = 8.3 Hz, 1 H); 6.95 (d, J = 8.8 Hz, 2 H); 7.68(dd, J = 2.0 and 8.3 Hz, 1 H); 7.82 502 (d, J = 2.0 Hz, 1 H); 9.36 (s, 1H); 12.80 (m, 1 H) 56

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2-isopropylphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 0.70 (d, J = 6.8 Hz, 3 H); 1.09 (d, J = 6.8 Hz, 3H); 1.63 (m, 1 H); 1.77 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.17 (m,3 H); 2.35 (m, 1 H); 2.43 (t, J = 7.2 Hz, 2 H); 2.50 (m, 1 H); 2.61 (m,1 H); 2.69 to 2.78 (m, 3 H); 3.11 (m, 1 H); 4.47 (td, J = 6.1 and 47.5Hz, 2 H); 4.71 (m, 1 H); 6.52 to 6.60 (m, 4 H); 6.68 (d, J = 8.8 Hz, 2H); 6.70 (d, J = 2.0 Hz, 1 H); 7.02 to 500 7.20 (m, 4 H); 9.36 (s, 1 H)57

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(o-tolyl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.01 to2.22 (m, 5 H); 2.12 (s, 3 H); 2.35 (m, 1 H); 2.44 (m, 2 H); 2.53 (m, 1H); 2.59 to 2.82 (m, 4 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m,1 H); 6.54 (d, J = 8.8 Hz, 2 H); 6.57 (s, 2 H); 6.66 (d, J = 8.8 Hz, 2H); 6.70 (s, 1 H); 6.99 to 7.11 (m, 4 H); 9.37 (s, 1 H) 472 58

6-(2- chlorophenyl)- 5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.06(m, 2 H); 2.18 (m, 3 H); 2.37 (m, 1 H); 2.44 (t, J = 7.2 Hz, 2 H); 2.52(m, 1 H); 2.61 (m, 1 H); 2.69 to 2.85 (m, 3 H); 4.46 (td, J = 6.1 and47.5 Hz, 2 H); 4.71 (m, 1 H); 6.57 (m, 4 H); 6.71 (m, 3 H); 7.08 to 7.20(m, 3 H); 7.39 (d, J = 8.2 Hz, 1 H); 9.40 (s, 1 H) 492 59

2-[5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 2-hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6- yl]-5-methoxy-benzonitrile A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.09 (m, 2 H); 2.14 to 2.26 (m, 3 H); 2.38 (m, 1H); 2.46 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64(m, 1 H); 2.80 (m, 3 H); 3.76 (s, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2H); 4.73 (m, 1 H); 6.57 (m, 2 H); 6.61 (d, J = 8.8 Hz, 2 H); 6.70 (d, J= 8.8 Hz, 2 H); 6.72 (s, 1 H); 7.17 (dd, J = 2.8 and 513 8.6 Hz, 1 H);7.21 (d, J = 2.8 Hz, 1 H); 7.33 (d, J = 8.6 Hz, 1 H); 9.44 (s, 1 H) 60

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-(trifluoromethyl) phenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2H); 2.02 to 2.27 (m, 5 H); 2.36 (m, 1 H); 2.43 (t, J = 7.2 Hz, 2 H);2.52 (m, 1 H); 2.58 to 2.69 (m, 2 H); 2.77 (m, 1 H); 2.85 (m, 1 H); 4.47(td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.57 (m, 4 H); 6.70 (m, 3H); 7.14 (d, J = 8.2 Hz, 1 H); 7.32 to 7.45 (m, 2 H); 7.69 (d, J = 8.2Hz, 1 H); 9.40 (s, 1 H) 526 61

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-fluoro-2- (trifluoromethyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.03 to 2.24 (m, 5 H); 2.37 (m, 1 H); 2.46 (t, J= 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.63 (m, 2 H); 2.73 to 2.80 (m, 2 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.55 (m, 2 H); 6.60(d, J = 8.8 Hz, 2 H); 6.69 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 7.20(dd, J = 6.0 and 8.8 Hz, 1 H); 7.32 (dt, J = 2.8 and 8.8 Hz, 1 544 H);7.60 (dd, J = 2.8 and 9.6 Hz, 1 H); 9.41 (s, 1 H) 62

6-(4- ethoxy- 2,5- difluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.30 (t, J = 7.0 Hz, 3 H); 1.69 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.11 to 2.23 (m, 3 H);2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.60 to 2.71(m, 3 H); 2.80 (dd, J = 6.4 and 10.5 Hz, 1 H); 4.04 (q, J = 7.0 Hz, 2H); 4.48 (td, J = 6.2 and 47.6 Hz, 2 H); 4.74 (m, 1 H); 6.57 (s, 2 H);6.62 (d, J = 8.9 Hz, 2 H); 6.70 (s, 1 H); 6.73 (d, J = 8.9 538 Hz, 2 H);6.92 (dd, J = 7.4 and 11.2 Hz, 1 H); 7.00 (dd, J = 7.0 and 11.8 Hz, 1H); 9.41 (s, 1 H) 63

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 6-(4-methoxy- 2-methyl- phenyl)- 8,9- dihydro- 7H- benzo[7] annulene-2-carboxylic acid hydrochloride B 1H NMR (500 MHz, DMSO-d6, δ ppm): 1.92to 2.30 (m, 8 H); 2.12 (s, 3 H); 2.89 (m, 2 H); 3.09 to 3.40 (m, 4 H);3.67 (m, 2 H); 3.70 (s, 3 H); 4.52 (td, J = 5.7 and 47.0 Hz, 2 H); 4.95to 5.08 (m, 1 H); 6.63 (dd, J = 2.6 and 8.5 Hz, 1 H); 6.68 (d, J = 9.0Hz, 2 H); 6.70 (d, J = 2.6 Hz, 1 H); 6.73 (d, J = 9.0 Hz, 2 H); 6.84 (d,J = 8.0 Hz, 1 H); 6.97 (d, J = 8.5 Hz, 1 H); 7.84 (dd, J = 1.9 and 8.0Hz, 1 H); 7.90 (d, J = 1.9 Hz, 1 H); 10.30 (s, 0.5 530 H); 10.64 (s, 0.5H); 12.86 (s, 1 H) 64

6-(2,4- dimethoxy phenyl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 1.99(m, 2 H); 2.09 (m, 2 H); 2.19 (m, 1 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2Hz, 2 H); 2.52 (m, 1 H); 2.59 to 2.71 (m, 3 H); 2.78 (dd, J = 6.4 and10.4 Hz, 1 H); 3.70 (s, 6 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71(m, 1 H); 6.29 (dd, J = 2.5 and 8.5 Hz, 1 H); 6.49 (d, J = 2.5 Hz, 1 H);6.54 (d, J = 1.5 Hz, 2 H); 518 6.56 (d, J = 8.8 Hz, 2 H); 6.68 (t, J =1.5 Hz, 1 H); 6.70 (d, J = 8.8 Hz, 2 H); 6.75 (d, J = 8.5 Hz, 1 H); 9.30(s, 1 H) 65

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-methoxy- 2- (trifluoromethyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.00 to 2.25 (m, 5 H); 2.37 (m, 1 H); 2.45 (t, J= 7.2 Hz, 2 H); 2.52 (m, 2 H); 2.62 (m, 1 H); 2.72 to 2.81 (m, 2 H);3.78 (s, 3 H); 4.45 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.55(s, 2 H); 6.59 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz,2 H); 7.00 (dd, J = 2.8 and 8.7 Hz, 1 H); 7.17 (d, J = 8.7 Hz, 556 1 H);7.27 (d J = 2.8 Hz, 1 H); 9.39 (s, 1 H) 66

6-[4- (difluoro- methoxy)-3- fluoro- phenyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.15 to 2.28 (m, 3 H); 2.39 (m, 1H); 2.48 (m, 2 H); 2.54 (m, 1 H); 2.68 (m, 3 H); 2.79 (dd, J = 6.3 and10.4 Hz, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.77 (m, 1 H); 6.56(s, 2 H); 6.64 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.74 (d, J = 8.8 Hz,2 H); 6.96 (d, J = 8.6 Hz, 1 H); 7.07 to 7.18 (m, 2 542 H); 7.19 (t, J =73.8 Hz, 1 H); 9.41 (s, 1 H) 67

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-methyl-4- (trifluoromethyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.78(dm, J = 25,3 Hz, 2 H); 2,01 to 2,25 (m, 5 H); 2,21 (s, 3 H); 2.36 (m, 1H); 2.45 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.59 to 2.81 (m, 4 H);4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.58 (m, 4 H); 6.66(d, J = 8.8 Hz, 2 H); 6.72 (s, 1 H); 7.22 (dd, J = 3.0 and 8.6 Hz, 1 H);7.38 (d, J = 8.6 Hz, 1 H); 7.47 (s, 1 H); 9.40 (s, 1 H) 540 68

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[6-(trifluoromethyl)- 3- pyridyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3Hz, 2 H); 2.08 (m, 2 H); 2.20 (m, 1 H); 2.31 (t, J = 7.0 Hz, 2 H); 2.38(m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1H); 2.65 (m, 1 H); 2.70 (t, J = 7.2 Hz, 2 H); 2.79 (dd, J = 6.3 and 10.4Hz, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.59 (s, 2H); 6.66 (d, J = 8.8 Hz, 2 H); 6.72 (s, 1 H); 6.76 527 (d, J = 8.8 Hz, 2H); 7.72 (d, J = 8.2 Hz, 1 H); 7.83 (dd, J = 2.5 and 8.2 Hz, 1 H); 8.40(d, J = 2.5 Hz, 1 H); 9.50 (s, 1 H) 69

6-[4- (difluoro- methoxy)phenyl]- 5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.04 (m, 2 H); 2.05 to 2.29 (m, 3 H); 2.39 (m, 1 H); 2.48 (m, 2H); 2.53 (m, 1 H); 2.65 (m, 3 H); 2.79 (m, 1 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.73 (m, 1 H); 6.55 (d, J = 1.5 Hz, 2 H); 6.61 (d, J =8.8 Hz, 2 H); 6.70 (d, J = 8.8 Hz, 2 H); 6.73 (s, 1 H); 6.97 (d, J = 8.5Hz, 2 H); 7.25 (d, J = 8.5 Hz, 2 H); 524 7.29 (t, J = 74.5 Hz, 1 H);9.38 (s, 1 H) 70

6-(2,2- dimethyl- indolin-5-yl)- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.13 (m, 2 H); 1.18 (s, 6 H); 1.65 to1.88 (m, 3 H); 2.01 (m, 2 H); 2.20 (m, 3 H); 2.33 to 2.70 (m, 7 H); 2.79(m, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 5.34 (s, 1H); 6.19 (d, J = 8.0 Hz, 1 H); 6.48 to 6.75 (m, 9 H); 9.28 (s, 1 H) 52771

6-(6- ethoxy-2- fluoro-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 0.77 (t, J = 7.1 Hz, 3 H); 1.71 (m, 1H); 1.81 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.17 (t, J = 7.0 Hz, 2H); 2.22 (m, 1 H); 2.35 to 2.93 (m, 6 H); 2.68 (t, J = 7.0 Hz, 2 H);4.18 (q, J = 7.1 Hz, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m,1 H); 6.55 (s, 2 H); 6.59 (d, J = 8.3 Hz, 1 H); 6.64 (d, J = 8.8 Hz, 2H); 6.70 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 7.58 521 (dd, J = 8.3 and10.2 Hz, 1 H); 9.42 (s, 1 H) 72

6-(4-tert- butylphenyl)- 5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.21 (s, 9 H); 1.70 (m, 1 H); 1.79 (dm, J = 25.3Hz, 2 H); 2.03 (m, 2 H); 2.20 (m, 1 H); 2.25 (t, J = 7.0 Hz, 2 H); 2.38(m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.2 and 10.4 Hz, 1H); 2.65 (m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J =6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.55 (m, 2 H); 6.59 (d, J = 8.8Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 514 Hz, 2 H); 7.03 (d, J = 8.6Hz, 2 H); 7.18 (d, J = 8.6 Hz, 2 H); 9.35 (s, 1 H) 73

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1,2,3,4- tetrahydro quinolin-6- yl)-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 to 1.88 (m, 5 H);2.00 (m, 2 H); 2.19 (m, 3 H); 2.39 (m, 1 H); 2.43 to 2.52 (m, 4 H); 2.55(dd, J = 3.0 and 10.4 Hz, 1 H); 2.59 to 2.69 (m, 3 H); 2.80 (dd, J = 6.4and 10.4 Hz, 1 H); 3.10 (m, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H);4.75 (m, 1 H); 5.52 (s, 1 H); 6.17 (d, J = 8.3 Hz, 1 H); 6.52 (m, 2 H);6.59 to 6.66 (m, 5 H); 6.74 (d, J = 8.8 Hz, 2 H); 513 9.28 (s, 1 H) 74

6-(3- ethoxyphenyl)- 5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.20 (t, J = 7.1 Hz, 3 H); 1.69 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.04 (m, 2 H); 2.19 (m, 1 H); 2.25 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.66(m, 3 H); 2.80 (dd, J = 6.4 and 10,4 Hz, 1 H); 3.82 (q, J = 7.1 Hz, 2H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.55 (m, 2 H);6.59 to 6.71 (m, 6 H); 6.73 (d, J = 8.8 Hz, 2 502 H); 7.07 (t, J = 8.0Hz, 1 H); 9.37 (s, 1 H) 75

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(trifluoromethoxy) phenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.28 (t, J = 7.0 Hz, 6 H); 1.70 (m, 1 H);1.80 (dm, J = 25.3 Hz, 2 H); 2.10 (m, 2 H); 2.20 (m, 1 H); 2.27 (t, J =7.0 Hz, 2 H); 2.41 (m, 1 H); 2.48 (m, 2 H); 2.57 (m, 1 H); 2.68 (m, 1H); 2.78 (t, J = 7.0 Hz, 2 H); 2.82 (m, 1 H); 4.17 (m, 4 H); 4.47 (td, J= 6.1 and 47.5 Hz, 2 H); 4.76 (m, 1 H); 6.64 (d, J = 8.8 Hz, 2 H); 6.73(d, J = 8.8 Hz, 2 H); 6.79 (d, J = 8.6 Hz, 1 542 H); 7.03 (ddd, J = 1.3and 2.8 and 8.6 Hz, 1 H); 7.16 (d, J = 2.8 Hz, 1 H); 7.18 (d, J = 8.9Hz, 2 H); 7.28 (d, J = 8.9 Hz, 2 H) 76

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-methoxyphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.03(m, 2 H); 2.17 (m, 1 H); 2.23 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.46(t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.65 (m, 3 H); 2.80 (dd, J = 6.4and 10.4 Hz, 1 H); 3.69 (s, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H);4.73 (m, 1 H); 6.54 (s, 2 H); 6.60 (d, J = 8.7 Hz, 2 H); 6.68 (s, 1 H);6.72 (m, 4 H); 7.04 (d, J = 8.7 Hz, 2 H); 9.31 488 (s, 1 H) 77

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(3-methoxyphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.04(m, 2 H); 2.19 (m, 1 H); 2.26 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.47(t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60 to 2.71(m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.49 (s, 3 H); 4.47 (td,J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.55 (s, 2 H); 6.61 (d, J =8.8 Hz, 2 H); 6.62 to 6.70 (m, 4 488 H); 6.73 (d, J = 8.8 Hz, 2 H); 7.08(m, 1 H); 9.38 (s, 1 H) 78

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(trifluoromoethyl) phenyl]-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2H); 2.03 (m, 2 H); 2.19 (m, 1 H); 2.29 (m, 2 H); 2.39 (m, 1 H); 2.48 to2.55 (m, 3 H); 2.60 to 2.71 (m, 3 H); 2.79 (m, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.57 (m, 2 H); 6.61 (d, J = 8.8 Hz, 2H); 6.72 (m, 3 H); 7.32 (d, J = 8.3 Hz, 2 H); 7.52 (d, J = 8.3 Hz, 2 H);9.43 (s, 1 H) 526 79

6-[4- (difluoro- methoxy)-3- fluoro- phenyl]-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.20 (m, 1 H); 2.28 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0and 10.4 Hz, 1 H); 2.65 (m, 1 H); 2.79 (m, 3 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.77 (m, 1 H); 6.40 (d, J = 8.6 Hz, 1 H); 6.65 (d, J =8.8 Hz, 2 H); 6.73 (t, J = 8.6 Hz, 1 H); 6.77 (d, J = 8.8 Hz, 2 H); 6.98(dd, J = 2.5 and 8.5 Hz, 1 H); 7.10 to 7.18 (m, 2 H); 7.19 (t, J = 73.5Hz, 1 H); 9.87 560 (m, 1 H) 80

6-(5- chloro-6- ethoxy-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.29 (t, J = 7.1 Hz, 3 H); 1.70 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.06 (m, 2 H); 2.15 to 2.18 (m, 3 H);2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.57 (dd, J = 3.2 and 10.4 Hz,1 H); 2.67 (m, 3 H); 2.79 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.30 (q, J =7.1 Hz, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1 H); 6.57(s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 537 (s, 1 H); 6.78 (d, J = 8.8Hz, 2 H); 7.60 (d, J = 2.4 Hz, 1 H); 7.80 (d, J = 2.4 Hz, 1 H); 9.42 (s,1 H) 81

6-(2- ethylphenyl)- 5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin-3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.08 (t, J = 7.6 Hz, 3 H); 1.65 (m, 1 H); 1.78(dm, J = 25.3 Hz, 2 H); 2.01 to 2.22 (m, 5 H); 2.35 (m, 1 H); 2.45 (t, J= 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.58 to 2.82 (m, 6 H); 4.46 (td, J = 6.1and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.54 (d, J = 8.8 Hz, 2 H); 6.57 (s, 2H); 6.65 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.98 to 7.05 (m, 2 H);7.11 (m, 1 H); 7.18 (d, J = 8.2 Hz, 486 1 H); 9.35 (s, 1 H) 82

6-(6- ethoxy-2- fluoro-3- pyridyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (t, J = 7.1 Hz, 3H); 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.13 to2.25 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J =3.0 and 10.4 Hz, 1 H); 2.63 (m, 1 H); 2.79 (m, 3 H); 4.19 (q, J = 7.1Hz, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.40 (d, J= 8.3 Hz, 1 H); 6.60 (dd, J = 1.4 and 8.3 Hz, 1 H); 6.64 (d, J = 8.8 Hz,2 H); 6.74 (m, 3 H); 7.59 (dd, J = 8.3 and 10.2 Hz, 1 H); 9.89 (m, 1 H)539 83

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2-methoxy- pyrimidin-5- yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.71 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2H); 2.08 (m, 2 H); 2.16 to 2.30 (m, 3 H); 2.39 (m, 1 H); 2.48 (m, 2 H);2.56 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.68 (m, 3 H); 2.80 (dd, J = 6.4and 10.4 Hz, 1 H); 3.86 (s, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H);4.78 (m, 1 H); 6.57 (s, 2 H); 6.69 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H);6.80 (d, J = 8.8 Hz, 2 H); 8.31 (s, 2 H); 9.46 490 (s, 1 H) 84

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-(trifluoromethyl) pyrimidin-5-yl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 to 1.86 (m, 3 H);2.10 (m, 2 H); 2.21 (m, 1 H); 2.30 to 2.58 (m, 6 H); 2.61 to 2.82 (m, 4H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.79 (m, 1 H); 6.59 (s, 2 H);6.69 (d, J = 8.8 Hz, 2 H); 6.72 (s, 1 H); 6.80 (d, J = 8.8 Hz, 2 H);8.74 (s, 2 H); 9.56 (s, 1 H) 528 85

2-fluoro-4- [5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 2- hydroxy- 8,9- dihydro- 7H- benzo[7] annule-6-yl]benzonitrile A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2H); 2.20 (m, 1 H); 2.29 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.48 (m, 2 H); 2.55 (m, 1 H); 2.79 (m, 3 H);2.80 (m, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1 H); 6.58(s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.73 (d, J = 8.8 Hz,2 H); 7.10 (d, J = 8.1 Hz, 1 H); 7.28 (d, J = 11.5 Hz, 1 H); 7.68 (t, J= 8.1 501 Hz, 1 H); 9.50 (s, 1 H) 86

6-(5- chloro-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.08(m, 2 H); 2.20 (m, 1 H); 2.29 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.48(t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.61 to 2.72(m, 3 H); 2.80 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.48 (td, J = 6.1 and47.5 Hz, 2 H); 4.78 (m, 1 H); 6.59 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H);6.71 (s, 1 H); 6.77 (d, J = 8.8 Hz, 493 2 H); 7.70 (d, J = 2.5 Hz, 1 H);8.18 (d, J = 2.5 Hz, 1 H); 8.31 (d, J = 2.5 Hz, 1 H); 9.49 (s, 1 H) 87

6-[6- (difluoro- methoxy)-3- pyridyl]-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.20 (m, 1 H); 2.28 (t, J = 7.0 Hz, 2 H); 2.39 (m,1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.56 (dd, J = 3.2 and 10.4 Hz, 1 H);2.68 (m, 3 H); 2.80 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.76 (m, 1 H); 6.56 (s, 2 H); 6.67 (d, J = 8.8 Hz, 2H); 6.71 (s, 1 H); 6.78 (d, J = 8.8 Hz, 2 H); 525 6.91 (d, J = 8.6 Hz, 1H); 7.62 (t, J = 73.1 Hz, 1 H); 7.68 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.96(d, J = 2.0 Hz, 1 H); 9.46 (s, 1 H) 88

6-(2,5- difluoro-4- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.04 (m, 2 H); 2.15 (t, J = 7.0 Hz, 2 H); 2.20 (m, 1 H); 2.39 (m,1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H);2.60 to 2.72 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.79 (s, 3H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.55 (s, 2 H);6.62 (d, J = 8.8 524 Hz, 2 H); 6.70 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H);6.93 (dd, J = 7.3 and 11.2 Hz, 1 H); 6.99 (dd, J = 7.1 and 12.1 Hz, 1H); 9.40 (s, 1 H) 89

6-(2- chloro-4- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.05 (m, 2 H); 2.12 to 2.23 (m, 3 H); 2.38 (m, 1 H); 2.45 (t, J =7.2 Hz, 2 H); 2.52 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.62 (m, 1 H); 2.70to 2.82 (m, 3 H); 3.71 (s, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H);4.72 (m, 1 H); 6.55 (s, 2 H); 6.59 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H);6.72 (dd, J = 2.6 and 522 8.8 Hz, 1 H); 6.73 (d, J = 8.8 Hz, 2 H); 6.97(d, J = 2.6 Hz, 1 H); 7.00 (d, J = 8.8 Hz, 1 H); 9.38 (s, 1 H) 90

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(5-fluoro-3- pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H);2.09 (m, 2 H); 2.20 (m, 1 H); 2.29 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H);2.47 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.1 and 10.4 Hz, 1 H); 2.61 to2.72 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.76 (m, 1 H); 6.58 (m, 2 H); 6.66 (d, J = 8.8 Hz, 2H); 6.71 (s, 1 H); 6.77 (d, J = 8.8 477 Hz, 2 H); 7.52 (td, J = 2.9 and10.4 Hz, 1 H); 8.09 (t, J = 2.9 Hz, 1 H): 8.27 (d, J = 2.9 Hz, 1 H);9.48 (s, 1 H) 91

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(6-methoxy- 4-methyl- 3-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.03 to 2.23 (m, 5 H); 2.12 (s, 3 H); 2.38 (m, 1 H); 2.45 (t, J =7.2 Hz, 2 H); 2.52 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64 (m, 2 H); 2.79(m, 2 H); 3.75 (s, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1H); 6.55 (s, 2 H); 6.57 (s, 1 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.69 (d, J= 8.8 Hz, 2 H); 6.71 (s, 1 H); 7.71 (s, 503 1 H); 9.39 (s, 1 H) 92

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-methoxy- 2,5- dimethyl- phenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3Hz, 2 H); 1.98 to 2.22 (m, 5 H); 2.01 (s, 3 H); 2.04 (s, 3 H); 2.37 (m,1 H); 2.45 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.71 (t,J = 7.0 Hz, 2 H, 1 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.71 (s, 3H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.54 (s, 2 H);6.55 (d, J = 8.8 Hz, 2 H); 6.61 (s, 1 H); 6.68 (d, J = 516 8.8 Hz, 2 H);6.81 (s, 1 H); 9.34 (s, 1 H) 93

6-(2,3- difluoro-4- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.05 (m, 2 H); 2.14 to 2.25 (m, 3 H); 2.39 (m, 1 H); 2.48 (t, J =7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.61 to 2.71 (m, 3H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.82 (s, 3 H); 4.47 (td, J =6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.57 (m, 2 H); 6.62 (d, J = 8.8Hz, 2 H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 524 H); 6.80 to 6.94 (m,2 H); 9.43 (s, 1 H) 94

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(trifluoro- methylsulfanyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.19 (m, 1 H); 2.29 (t, J = 7.0Hz, 2 H); 2.38 (m, 1 H); 2.45 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.2and 10.4 Hz, 1 H); 2.60 to 2.71 (m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz,1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.57 (s, 2 H);6.60 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.71 (d, J = 8.8 Hz, 2 558 H);7.25 (d, J = 8.4 Hz, 2 H); 7.50 (d, J = 8.4 Hz, 2 H); 9.46 (s, 1 H) 95

6-(3- chloro-4- ethoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annune-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.31 (t, J = 7.1 Hz, 3 H); 1.70 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.15 to 2.27 (m, 3 H);2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.1 and 10.4 Hz,1 H); 2.66 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.03 (q, J =7.1 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.54(s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.69 536 (s, 1 H); 6.75 (d, J = 8.8Hz, 2 H); 6.92 (d, J = 8.6 Hz, 1 H); 7.03 (dd, J = 2.6 and 8.6 Hz, 1 H);7.11 (d, J = 2.6 Hz, 1 H); 9.38 (s, 1 H) 96

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(5-methyl-3- pyridyl)- 8,9- dihydro- 7H- benzo[7] annune-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.05(m, 2 H); 2.19 (m, 1 H); 2.20 (s, 3 H); 2.26 (t, J = 7.0 Hz, 2 H); 2.39(m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1H); 2.61 to 2.71 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47(td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.57 (m, 2 H); 6.63 (d, J= 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.74 473 (d, J = 8.8 Hz, 2 H); 7.42 (t, J= 2.3 Hz, 1 H); 8.01 (d, J = 2.3 Hz, 1 H); 8.10 (d, J = 2.3 Hz, 1 H);9.43 (s, 1 H) 97

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl[oxyphenyl]- 6-(6-methoxy- 2-methyl- 3-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6), δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.03 to 2.24 (m, 5 H); 2.20 (s, 3 H); 2.38 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.71 (t, J = 7.2 Hz, 2 H);2.79 (dd, J = 6.3 and 10.4 Hz, 1 H); 3.77 (s, 3 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.51 (d, J = 8.4 Hz, 1 H); 6.55 (s, 2H); 6.60 (d, J = 9.0 Hz, 2 H); 6.69 (d, J = 9.0 Hz, 503 2 H); 6.71 (s, 1H); 7.33 (d, J = 8.4 Hz, 1 H); 9.41 (s, 1 H) 98

6-(2,2- dimethyl- 3H- benzofuran- 5-yl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 Mhz, DMSO-d6, δ ppm): 1.35 (s, 6 H); 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.13 to 2.25 (m, 3 H); 2.39 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60to 2.71 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 2.84 (s, 2 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.76 (m, 1 H); 6.47 (d, J = 8.3 Hz,1 H); 6.54 (m, 2 H); 6.61 528 (d, J = 8.8 Hz, 2 H); 6.68 (s, 1 H); 6.72(d, J = 8.8 Hz, 2 H); 6.81 (dd, J = 2.5 and 8.3 Hz, 1 H); 6.91 (d, J =2.5 Hz, 1 H); 9.33 (s, 1 H) 99

6-(5- chloro-6- methoxy- 3-pyridyl)- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.20 (m, 1 H); 2.33 (t, J = 7.2 Hz, 2 H); 2.39 (m,1 H); 2.48 (t, J = 7.3 Hz, 2 H); 2.55 (dd, J = 3.2 and 10.5 Hz, 1 H);2.61 to 2.70 (m, 3 H); 2.80 (dd, J = 6.1 and 10.5 Hz, 1 H); 3.86 (s, 3H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.79 (m, 1 H); 6.56 (s, 2 H);6.69 (d, J = 8.9 Hz, 2 H); 6.70 (s, 1 H); 6.79 523 (d, J = 8.9 Hz, 2 H);7.61 (dd, J = 2.3 Hz, 1 H); 7.82 (d, J = 2.3 Hz, 1 H); 9.43 (s, 1 H) 100

6-(4- ethoxy- 2,5- dimethyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.31 (t, J = 7.1 Hz, 3 H); 1.68 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.01 (s, 6 H); 2.03 (m, 2 H); 2.10 (m,2 H); 2.19 (m, 1 H); 2.37 (m, 1 H); 2.45 (t, J = 7.2 Hz, 2 H); 2.52 (dd,J = 3.0 and 10.4 Hz, 1 H); 2.61 (m, 1 H); 2.70 (m, 2 H); 2.79 (dd, J =6.3 and 10.4 Hz, 1 H); 3.95 (m, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2H); 4.71 (m, 1 H); 6.53 530 (s, 2 H); 6.55 (d, J = 8.8 Hz, 2 H); 6.60(s, 1 H); 6.67 (d, J = 8.8 Hz, 2 H); 6.69 (t, J = 1.0 Hz, 1 H); 6.80 (s,1 H); 9.33 (s, 1 H) 101

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(6-methoxy- 5-methyl- 3-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.03 (s, 3 H); 2.05 (m, 2 H); 2.15 to 2.25 (m, 3 H); 2.38 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64(m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.79 (s, 3 H); 4.46 (td,J = 6.1 and 47.5 Hz, 2 H); 4.76 (m, 1 H); 6.54 (s, 2 H); 6.65 (d, J =8.8 Hz, 2 H); 6.70 (s, 1 H); 6.76 (d, J = 8.8 Hz, 2 503 H); 7.32 (d, J =3.0 Hz, 1 H); 7.67 (d, J = 3.0 Hz, 1 H); 9.39 (s, 1 H) 102

6-(5-fluoro- 6- methoxy- 3-pyridyl)- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.06 (m, 2 H); 2.13 to 2.28 (m, 3 H); 2.38 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.68 (m, 3 H); 2.80(dd, J = 6.4 and 10.4 Hz, 1 H); 3.86 (s, 3 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.78 (m, 1 H); 6.56 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H);6.70 (s, 1 H); 6.79 (d, J = 8.8 Hz, 2 H); 507 7.42 (dd, J = 2.0 and 11.9Hz, 1 H); 7.68 (d, J = 2.0 Hz, 1 H); 9.42 (s, 1 H) 103

6-(3- chloro-4- ethoxy-2- fluoro- phenyl)-5- [4-(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.33 (t, J = 7.2 Hz, 3H); 1.68 (m, 1 H); 1.81 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.16 to2.23 (m, 3 H); 2.40 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J =3.0 and 10.4 Hz, 1 H); 2.63 (m, 1 H); 2.68 (t, J = 7.0 Hz, 2 H); 2.79(dd, J = 6.4 and 10.4 Hz, 1 H); 4.10 (q, J = 7.2 Hz, 2 H); 4.47 (td, J =6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.56 (m, 2 H); 6.63 (d, 554 J =8.8 Hz, 2 H); 6.71 (s, 1 H); 6.73 (d, J = 8.8 Hz, 2 H); 6.83 (d, J = 9.0Hz, 1 H); 7.03 (t, J = 9.0 Hz, 1 H); 9.40 (s, 1 H) 104

6-(2-fluoro- 6- methoxy- 3-pyridyl)- 5-[4-[(3S)- 1-93- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.05 (m, 2 H); 2.13 to 2.25 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.54 (dd, J = 3.1 and 10.4 Hz, 1 H); 2.60 to 2.71 (m, 3H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.78 (s, 3 H); 4.48 (td, J =6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.56 (s, 2 H); 6.61 (d, J = 8.2Hz, 1 H); 6.64 (d, J = 8.8 Hz, 2 H); 6.70 507 (s, 1 H); 6.74 (d, J = 8.8Hz, 2 H); 7.59 (dd, J = 8.2 and 10.1 Hz, 1 H); 9.44 (s, 1 H) 105

6-(3,5- difluoro-4- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.05 (m, 2 H); 2.21 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz,2 H); 2.53 (dd, J = 3.2 and 10.5 Hz, 1 H); 2.66 (m, 3 H); 2.80 (dd, J =6.2 and 10.5 Hz, 1 H); 3.85 (s, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2H); 4.79 (m, 1 H); 6.55 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1H); 6.76 (d, J = 8.8 Hz, 2 H); 6.83 (d, J = 10.0 Hz, 524 2 H); 9.44 (s,1 H) 106

6-(1- ethylindolin- 5-yl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.07 (t, J = 7.4 Hz, 3 H); 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.00 (m, 2 H); 2.20 (m, 3 H); 2.38 (m, 1 H);2.47 (m, 2 H); 2.54 (m, 1 H); 2.65 (m, 3 H); 2.74 (t, J = 7.2 Hz, 2 H);2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.02 (q, J = 7.4 Hz, 2 H); 3.22 (t,J = 7.2 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H);6.25 (d, J = 8.2 Hz, 1 H); 6.52 (s, 2 H); 6.60 527 (d, J = 8.8 Hz, 2 H);6.65 (s, 1 H); 6.73 (m, 3 H); 6.81 (s, 1 H); 9.29 (s, 1 H) 107

6-(2- ethoxypyrimidin- 5- yl)-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (t, J = 7.1 Hz, 3 H); 1.65 to1.88 (m, 3 H); 2.08 (m, 2 H); 2.16 to 2.29 (m, 3 H); 2.35 to 2.58 (m, 4H); 3.68 (m, 3 H); 2.80 (m, 1 H); 4.27 (q, J = 7.1 Hz, 2 H); 4.47 (td, J= 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1 H); 6.57 (s, 2 H); 6.69 (d, J = 8.8Hz, 2 H); 6.71 (s, 1 H); 6.80 (d, J = 8.8 Hz, 2 H); 8.29 (s, 2 H); 9.46(s, 1 H) 504 108

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(6-methoxy- 3-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H);2.05 (m, 2 H); 2.15 to 2.27 (m, 3 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2Hz, 2 H); 2.54 (dd, J = 3.2 and 10.4 Hz, 1 H); 2.65 (m, 3 H); 2.80 (dd,J = 6.4 and 10.3 Hz, 1 H); 3.78 (s, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz,2 H); 4.75 (m, 1 H); 6.56 (s, 2 H); 6.63 (m, 3 H); 6.70 (s, 1 H); 6.75(d, J = 8.8 Hz, 2 H); 7.45 (dd, 489 J = 2.5 and 8.7 Hz, 1 H); 7.89 (d, J= 2.5 Hz. 1 H); 9.40 (s, 1 H) 109

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2-methoxy- 4-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H);2.02 (m, 2 H); 2.15 to 2.27 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2Hz, 2 H); 2.55 (dd, J = 3.0 and 10.5 Hz, 1 H); 2.64 (m, 3 H); 2.80 (dd,J = 6.4 and 10.4 Hz, 1 H); 3.76 (s, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz,2 H); 4.78 (m, 1 H); 6.51 (s, 1 H); 6.57 (m, 2 H); 6.67 (m, 3 H); 6.70(s, 1 H); 6.76 (d, J = 8.8 Hz, 2 489 H); 7.92 (d, J = 5.4 Hz, 1 H); 9.47(s, 1 H) 110

6-(6- ethoxy-5- methyl-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.36 (t, J = 7.3 Hz, 3 H); 1.70 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.02 (s, 3 H); 2.04 (m, 2 H); 2.15 to2.25 (m, 3 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J =3.1 and 10.4 Hz, 1 H); 2.66 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1H); 4.22 (q, J = 7.3 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.76(m, 1 H); 6.55 (s, 2 H); 6.64 (d, J = 8.8 Hz, 2 517 H); 6.79 (s, 1 H);6.75 (d, J = 8.8 Hz, 2 H); 7.32 (d, J = 2.6 Hz, 1 H); 7.62 (d, J = 2.6Hz, 1 H); 9.39 (s, 1 H) 111

6-(3-fluoro- 4- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.04 (m, 2 H); 2.15 to 2.27 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.54 (m, dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H);2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.77 (s, 3H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.76 (m, 1 H); 6.54 (s, 2 H); 6.63 (d, J = 8.8 Hz, 2 H);6.69 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 506 6.86,85 to 6.92 (m, 2 H);6.95 (t, J = 8.7 Hz, 1 H); 9.38 (s, 1 H) 112

6-(2,4- difluoro-3- methoxy- phenyl)-5- [4-[(3S)-1- (3- fluoroproyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.18 (m, 3 H); 2.39 (m, 1 H); 2.45 (t, J = 7.2 Hz,2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.69 (t, J = 7.0 Hz, 2 H); 2.79 (dd,J = 6.4 and 10.4 Hz, 1 H); 3.74 (s, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz,2 H); 4.72 (m, 1 H); 6.58 (s, 2 H); 6.61 (d, J = 8.8 Hz, 2 H); 6.71 (m,3 H); 6.90 (ddd, J = 6.2 and 8.5 and 9.0 Hz, 1 524 H); 6.98 (ddd, J =2.2 and 9.0 and 11.0 Hz, 1 H); 9.43 (s, 1 H) 113

6-(4- chloro-3- methyl- phenyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.18 (m, 1 H); 2.20 (s, 3 H);2.26 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H);2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 1 H); 2.73 to 2.82 (m, 3H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.77 (m, 1 H); 6.40 (d, J = 8.7Hz, 1 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.72 (t, J = 8.7 Hz, 1 H); 6.75 (d,J = 8.8 Hz, 2 H); 6.91 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.13 (d, 524 J =2.5 Hz, 1 H); 7.18 (d, J = 8.5 Hz, 1 H); 9.80 (m, 1 H) 114

1-fluoro-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]-6-[4- (trifluoromethoxy) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.19 (m, 1 H); 2.29 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.45 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.2and 10.4 Hz, 1 H); 2.63 (m, 1 H); 2.79 (m, 3 H); 4.46 (td, J = 6.1 and47.5 Hz, 2 H); 4.73 (m, 1 H); 6.40 (d, J = 8.3 Hz, 1 H); 6.61 (d, J =8.8 Hz, 2 H); 6.72 (m, 3 H); 7.15 (d, J = 8.9 Hz, 2 H); 7.23 (d, J = 8.9Hz, 2 H); 9.79 (s, 1 H) 560 115

1-fluoro-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]-6-[4- fluoro-2- (trifluoromethyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.08 (m, 2 H); 2.18 (m, 3 H); 2.37 (m, 1 H);2.45 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.59 to 2.81 (m, 3 H); 2.99(s, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.40 (d, J= 8.6 Hz, 1 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.70 (d, J = 8.8 Hz, 2 H);6.74 (t, J = 8.6 Hz, 1 H); 7.21 (dd, J = 6.0 and 8.9 Hz, 1 H); 7.32 (dt,J = 3.0 and 8.9 Hz, 1 H); 7.60 (dd, J = 3.0 and 9.5 Hz, 1 H); 9.80 562(s, 1 H) 116

6-[4- (difluoro- methoxy)- 2- fluoro- phenyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.12 to 2.25 (m, 3 H); 2.38 (m, 1H); 2.45 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.59to 2.72 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.56 (m, 2 H); 6.61 (d, J = 8.8 Hz, 2H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.87 (dd, 542 J = 2.7 and8.7 Hz, 1 H); 6.97 (dd, J = 2.7 and 10.7 Hz, 1 H); 7.20 (t, J = 8.7 Hz,1 H); 7.23 (t, J = 73.8 Hz, 1 H); 9.43 (s, 1 H) 117

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-fluoro-4- (trifluoromethoxy) phenyl]-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.07 (m, 2 H); 2.19 (m, 3 H); 2.38 (m, 1 H);2.46 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.63 (m, 1 H); 2.71 (t, J =7.0 Hz, 2 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.72 (m, 1 H); 6.58 (s, 2 H); 6.61 (d, J = 8.8 Hz, 2 H);6.70 (d, J = 8.8 Hz, 2 H); 6.72 (s, 1 H); 7.08 (d, J = 8.6 Hz, 1 560 H);7.22 (d, J = 10.2 Hz, 1 H); 7.29 (t, J = 8.6 Hz, 1 H); 9.44 (s, 1 H) 118

6-(2,6- dichloro-3- pyridyl)-5- [4-(3S)-1- (3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, d ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.03to 2.17 (m, 5 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1H); 2.63 (m, 1 H); 2.78 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H);4.74 (m, 1 H); 6.57 (s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H);6.73 (d, J = 8.8 Hz, 2 H); 7.41 (d, J = 8.7 Hz, 1 H); 7.68 (d, J = 8.7Hz, 1 H); 9.99 (s, 1 H) 527 119

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(2,2,2- trifluoroethoxy) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.71 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.02 (m, 2 H); 2.13 to 2.27 (m, 3 H); 2.40 (m, 1H); 2.48 (m, 2 H); 2.55 (m, 1 H); 2.65 (m, 3 H); 2.80 (m, 1 H); 4.47(td, J = 6.1 and 47.5 Hz, 2 H); 4.68 (q, J = 8.9 Hz, 2 H); 4.74 (m, 1H); 6.54 (s, 2 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J= 8.8 Hz, 2 H); 6.85 (d, J = 9.0 Hz, 2 H); 7.08 (d, J = 9.0 Hz, 556 2H); 9.34 (s, 1 H) 120

6-(4- ethoxy- 3,5- difluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.34 (t, J = 7.2 Hz, 3 H); 1.70 (m, 1H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.27 to 2.37 (m, 3 H);2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.56 (dd, J = 3.0 and 10.4 Hz,1 H); 2.67 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.09 (q, J =7.2 Hz, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.55(s, 2 H); 6.67 (d, J = 8.8 Hz, 2 H); 6.69 538 (s, 1 H); 6.74 (d, J = 8.8Hz, 2 H); 6.82 (d, J = 9.9 Hz, 2 H); 9.41 (s, 1 H) 121

6-(4- chloro-2- fluoro- phenyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.19 (m, 3 H); 2.38 (m, 1 H);2.47 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.2 and 10.4 Hz, 1 H); 2.63 (m,1 H); 2.79 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H);6.42 (d, J = 8.0 Hz, 1 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.72 (m, 3 H);7.12 (dd, J = 2.5 and 8.3 Hz, 1 H); 7.20 (t, J = 8.3 Hz, 1 H); 7.29 (dd,J = 2.2 and 9.8 Hz, 1 H); 9.87 (s, 1 H) 528 122

6-(2- chloro-3- fluoro- phenyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.07 (m, 2 H); 2.19 (m, 3 H); 2.36 (m, 1 H);2.44 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.62 (m, 1 H); 2.77 (m, 2 H);2.99 (m, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.41(d, J = 8.6 Hz, 1 H); 6.61 (d, J = 8.8 Hz, 2 H); 6.73 (d, J = 8.8 Hz, 2H); 6.75 (t, J = 8.6 Hz, 1 H); 7.00 (m, 1 H); 7.20 (m, 2 H); 9.87 (s, 1H) 528 123

1-fluoro-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]-6-[2- methyl-4- (trifluoromethyl) phenyl]-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.78(dm, J = 25.3, 2 H); 2.07 (m, 2 H); 2.18 (m, 3 H); 2.22 (s, 3 H); 2.35(m, 1 H); 2.43 (t, J = 7.2 Hz, 2 H); 2.51 (m, 1 H); 2.62 (m, 1 H); 2.77(m, 1 H); 2.87 (m, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1H); 6.41 (d, J = 8.8 Hz, 1 H); 6.58 (d, J = 8.8 Hz, 2 H); 6.67 (d, J =8.8 Hz, 2 H); 6.75 (t, J = 8.8 Hz, 1 H); 7.22 (dd, J = 3.1 and 7.9 Hz, 1H); 7.38 (d, J = 7.9 Hz, 1 H); 7.48 (s, 1 H); 9.82 (s, 1 H) 558 124

1-fluoro-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]-6-[4- (trifluoromethyl) phenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3Hz, 2 H); 2.04 (m, 2 H); 2.19 (m, 1 H); 2.30 (t, J = 7.0 Hz, 2 H); 2.38(m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1H); 2.63 (m, 1 H); 2.79 (m, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H);4.74 (m, 1 H); 6.41 (d, J = 8.7 Hz, 1 H); 6.63 (d, J = 8.8 Hz, 2 H);6.74 (t, J = 8.7 Hz, 1 H); 6.75 (d, J = 8.8 Hz, 2 H); 7.35 (d, J = 8.7Hz, 2 H); 7.53 (d, J = 8.7 Hz, 2 H); 9.88 (s, 1 H) 544 125

6-(6- ethoxy-2- methyl-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.25 (t, J = 7.1 Hz, 3 H); 1.69 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.03 to 2.23 (m, 5 H); 2.15 (s, 3 H);2.33 to 2.58 (m, 4 H); 2.60 to 2.73 (m, 4 H); 4.20 (q, J = 7.1 Hz, 2 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.48 (d, J = 8.7 Hz,1 H); 6.55 (s, 2 H); 6.60 (d, J = 8.8 Hz, 2 H); H); 6.71 (s, 1 H); 7.32(d, J = 8.7 Hz, 1 H); 9.38 (s, 1 H) 517 126

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1-methylindol- 5-yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.02(m, 2 H); 2.17 (m, 1 H); 2.31 (t, J = 7.0 Hz, 2 H); 2.37 (m, 1 H); 2.44(t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.61 (m, 1 H); 2.69 (t, J = 7.0 Hz,2 H); 2.76 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.71 (s, 3 H); 4.45 (td, J =6.1 and 47.5 Hz, 2 H); 4.69 (m, 1 H); 6.27 (d, J = 3.2 Hz, 1 H); 6.63(d, J = 8.8 Hz, 2 H); 6.65 (s, 2 H); 6.69 511 (s, 1 H); 6.73 (d, J = 8.8Hz, 2 H); 6.93 (dd, J = 1.8 and 8.6 Hz, 1 H); 7.19 (d, J = 8.6 Hz, 1 H);7.22 (d, J = 3.2 Hz, 1 H); 7.32 (d, J = 1.8 Hz, 1 H); 9.32 (s, 1 H) 127

6-(6- chloro-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin-3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.05(m, 2 H); 2.21 (m, 1 H); 2.27 (t, J = 7.0 Hz, 2 H); 2.35 to 2.59 (m, 4H); 2.69 (m, 3 H); 2.81 (m, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H);4.77 (m, 1 H); 6.57 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H);6.77 (d, J = 8.8 Hz, 2 H); 7.34 (d, J = 8.3 Hz, 1 H); 7.62 (dd, J = 2.6and 8.3 Hz, 1 H); 8.08 (d, J = 2.6 Hz, 493 1 H); 9.46 (s, 1 H) 128

2-fluoro-4- [5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl- 2- hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6- yl]-N-methyl- benzamide A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H);1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2 H); 2.30 (m, 3 H); 2.39(m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1H); 2.67 (m, 3 H); 2.74 (d, J = 4.8 Hz, 3 H); 2.80 (dd, = 6.4 and 10.4Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.77 (m, 1 H); 6.56 (s, 2H); 6.65 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 6.76 (d, J = 8.8 Hz, 2 :533 H); 6.98 (dd, J = 1.6 and 4.8 Hz, 1 H); 7.01 (s, 1 H); 7.42 (t, J =8.1 Hz, 1 H); 8.09 (m, 1 H); 9.43 (s, 1 H) 129

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-fluoro-6- (trifluoromethyl)- 3- pyridyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.10 (m, 2 H); 2.20 (m, 1 H); 2.26 (t, J = 7.0Hz, 2 H); 2.40 (m, 1 H); 2.48 (t, J = 7.0 Hz, 2 H); 2.54 (m, 1 H); 2.66(m, 1 H); 2.71 (t, J = 7.0 Hz, 2 H); 2.79 (m, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.59 (s, 2 H); 6.66 (d, J = 8.8 Hz, 2H); 6.72 (d, J = 8.8 Hz, 2 H); 6.74 (s, 1 H); 7.74 (dd, J = 17 and 8.2545 Hz, 1 H); 8.02 (t, J = 8.2 Hz, 1 H); 9.50 (s, 1 H) 130

6-[4-(2- fluoroethoxy) phenyl]- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.03 (m, 2 H); 2.15 to 2.27 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64 (m, 3 H); 2.79(dd, J = 6.4 and 10.4 Hz, 1 H); 4.16 (dm, J = 30.3 Hz, 2 H); 4.47 (td, J= 6.1 and 47.5 Hz, 2 H); 4.69 (dm, J = 48.6 Hz, 2 H); 4.74 (m, 1 H);6.54 (s, 2 H); 6.61 (d, J = 8.8 Hz, 2 H); 520 6.68 (s, 1 H); 6.72 (d, J= 8.8 Hz, 2 H); 6.76 (d, J = 8.9 Hz, 2 H); 7.04 (d, J = 8.9 Hz, 2 H);9.31 (s, 1 H) 131

6-(4- ethoxy- 2,3- dimethyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 0.80 (t, J = 7.1 Hz, 3 H); 1.68 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.02 (m, 2 H); 2.03 (s, 3 H); 2.10 (s,3 H); 2.12 to 2.22 (m, 3 H); 2.25 to 2.58 (m, 4 H); 2.63 (m, 2 H); 2.79(m, 2 H); 3.92 (m, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1H); 6.54 (d, J = 8.8 Hz, 2 H); 6.56 (s, 2 H); 6.59 (d, J = 8.6 Hz, 1 H);6.65 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 530 6.72 (d, J = 8.6 Hz, 1 H);9.30 (s, 1 H) 132

6-[6- ethoxy-5- (trifluoromethyl)- 3- pyridyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (t, J = 7.1 Hz, 3H); 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.08 (m, 2 H); 2.20 (m,1 H); 2.30 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60 to 2.71 (m, 3 H); 2.79(dd, J = 6.4 and 10.4 Hz, 1 H); 4.37 (q, J = 7.1 Hz, 2 H); 4.47 (td, J =6.1 and 47.5 Hz, 2 H); 4.79 (m, 1 H); 6.58 (m, 2 H); 6.69 (d, 571 J =8.8 Hz, 2 H); 6.71 (m, 1 H); 6.78 (d, J = 8.8 Hz, 2 H); 7.68 (d, J = 2.7Hz, 1 H); 8.15 (d, J = 2.7 Hz, 1 H); 9.43 (s, 1 H) 133

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-methyl- 2,3- dihydro- 1,4- benzoxazin- 7-yl)-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.71 (m, 1 H); 1.81(dm, J = 25.3 Hz, 2 H); 2.00 (m, 2 H); 2.15 to 2.25 (m, 3 H); 2.40 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.56 (dd, J = 3.2 and 10.4 Hz, 1 H); 2.60to 2.71 (m, 3 H); 2.76 (s, 3 H); 2.81 (dd, J = 6.4 and 10.4 Hz, 1 H);3.17 (m, 2 H); 4.12 (m, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75(m, 1 H); 6.42 (d, J = 2.2 Hz, 1 H); 6.47 (d, J = 8.5 Hz, 1 529 H); 6.52(s, 2 H); 6.53 (dd, J = 2.2 and 8.5 Hz, 1 H); 6.62 (d, J = 8.8 Hz, 2 H);6.65 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 9.28 (s, 1 H) 134

6-(2,2- difluoro- 1,3- benzodioxol- 5-yl)-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.19 (m, 1 H); 2.25 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0and 10.4 Hz, 1 H); 2.61 to 2.71 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz,1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.56 (s, 2 H);6.64 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.75 (d, J = 8.8 Hz, 2 538 H);6.92 (dd, J = 2.0 and 8.5 Hz, 1 H); 7.25 (d, J = 2.0 Hz, 1 H); 7.28 (d,J = 8.5 Hz, 1 H); 9.39 (s, 1 H) 135

4-ethyl-6- [5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 2- hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6-yl]-1,4- benzoxazin- 3-one A 1H NMR (400 MHz, DMSO-d6, δ ppm): 0.80 (t,J = 7.1 Hz, 3 H); 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2H); 2.19 (m, 1 H); 2.28 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.46 (t, J= 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.60 to 2.72 (m, 3 H); 2.79 (dd, J = 6.4and 10.4 Hz, 1 H); 3.67 (q, J = 7.1 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5Hz, 2 H); 4.55 (s, 2 H); 4.73 (m, 1 H); 6.55 (s, 2 H); 6.65 (d, J = 8.8557 Hz, 2 H); 6.69 (s, 1 H); 6.78 (d, J = 8.8 Hz, 2 H); 6.82 (s, 1 H);6.85 (s, 2 H); 9.38 (s, 1 H) 136

6-[2- chloro-4- (trifluoromethoxy) phenyl]-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.08 (m, 2 H); 2.19 (m, 3 H); 2.36 (m, 1 H);2.45 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.78 (m, 3 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.57 (s, 2 H); 6.59(d, J = 8.8 Hz, 2 H); 6.70 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 7.19 (d,J = 8.3 Hz, 1 H); 7.25 (d, J = 8.3 Hz, 1 H); 7.50 (s, 1 H); 576 9.45 (s,1 H) 137

6-[4- (difluoro- methoxy)- 3,5- difluoro- phenyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.16 to 2.28 (m, 3 H); 2.39 (m, 1H); 2.48 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.67(m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.48 (td, J = 6.1 and47.5 Hz, 2 H); 4.78 (m, 1 H); 6.57 (s, 2 H); 6.68 (d, J = 8.8 Hz, 2 H);6.69 (s, 1 H); 6.78 (d, J = 8.8 Hz, 2 H); 6.99 (d, J = 8.4 Hz, 560 2 H);7.19 (t, J = 72.5 Hz, 1 H); 9.38 (s, 1 H) 138

6-(4-tert- butylphenyl)- 1-fluoro- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.22 (s, 9 H); 1.70 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.19 (m, 1 H); 2.25 (t, J = 7.0Hz, 2 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.65(m, 1 H); 2.77 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1H); 6.39 (d, J = 8.5 Hz, 1 H); 6.59 (d, J = 8.8 Hz, 2 H); 6.72 (m, 3 H);7.04 (d, J = 8.5 Hz, 2 H); 7.19 (d, J = 8.5 Hz, 2 H); 9.74 (s, 1 H) 532139

6-(6- ethoxy-4- methyl-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.25 (t, J = 7.2 Hz, 3 H); 1.69 (m, 1H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.01 to 2.25 (m, 5 H); 2.12 (s, 3 H);2.35 to 2.88 (m, 8 H); 4.19 (m, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2H); 4.74 (m, 1 H); 6.54 (s, 2 H); 6.56 (s, 2 H); 6.60 (d, J = 8.8 Hz, 2H); 6.69 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 7.70 (s, 1 H); 9.38 (s, 1H) 517 140

6-(3- chloro-4- ethoxy-5- fluoro- phenyl)-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.25 (t, J = 7.2 Hz, 3H); 1.70 (m, 1 H); 1.81 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.15 to2.17 (m, 3 H); 2.39 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.55 (dd, J =3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1H); 4.05 (q, J = 7.2 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78(m, 1 H); 6.56 (m, 2 H); 6.67 (d, J = 8.8 Hz, 2 H); 6.68 554 (s, 1 H);6.75 (d, J = 8.8 Hz, 2 H); 6.97 (dd, J = 2.5 and 12.5 Hz, 1 H); 6.99 (t,J = 2.5 Hz, 1 H); 9.42 (s, 1 H) 141

6-(2- aminopyrimindin- 5- yl)-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.71 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.08 (m, 2 H); 2.17 to 2.26 (m, 3 H); 2.40 (m, 1 H); 2.48 (t, J =7.2 Hz, 2 H); 2.57 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H); 2.82(dd, J = 6.4 and 10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H);4.78 (m, 1 H); 6.43 (s, 2 H); 6.55 (s, 2 H); 6.68 (s, 1 H); 6.69 (d, J =8.8 Hz, 2 H); 6.81 (d, J = 8.8 Hz, 2 H); 475 7.95 (s, 2 H); 9.34 (s, 1H) 142

6-[4- (difluoromethyl) phenyl]-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.04 (m, 2 H); 2.19 (m, 1 H); 2.29 (t, J = 7.0 Hz, 2 H); 2.39 (m,1 H); 2.48 (m, 2 H); 2.55 (m, 1 H); 2.68 (m, 3 H); 2.80 (m, 1 H); 4.47(td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.56 (s, 2 H); 6.61 (d, J= 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.92 (t, J =56.1 Hz, 1 H); 7.24 (d, J = 8.3 Hz, 2 H); 7.36 (d, 508 J = 8.3 Hz, 2 H);9.40 (s, 1 H) 143

6-[4- (difluoromethoxy) phenyl]-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.03 (m, 2 H); 2.20 (m, 1 H); 2.26 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0and 10.4 Hz, 1 H); 2.65 (m, 1 H); 2.78 (m, 3 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.73 (m, 1 H); 6.40 (d, J = 8.6 Hz, 1 H); 6.61 (d, J =8.8 Hz, 2 H); 6.73 (d, J = 8.8 Hz, 3 H); 6.98 (d, J = 8.8 Hz, 2 H); 7.18(d, J = 8.8 Hz, 2 H); 7.19 (t, J = 74.3 Hz, 1 H); 9.80 (s, 1 H) 542 144

6-[3,5- difluoro-4- (trifluoromethoxy) phenyl]-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.06 (m, 2 H); 2.20 (m, 1 H); 2.25 (t, J = 7.0Hz, 2 H); 2.39 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0and 10.4 Hz, 1 H); 2.67 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.79 (m, 1 H); 6.57 (s, 2 H); 6.69(d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 6.76 (d, J = 8.8 Hz, 2 H); 578 7.10(d, J = 9.8 Hz, 2 H); 9.48 (s, 1 H) 145

6-[4- (difluoro- methoxy)-2- methyl- phenyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.02 to 2.23 (m, 5 H); 2.12 (s, 3 H); 2.37 (m, 1H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.59 to 2.81 (m, 4 H);4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.56 (s, 2 H); 6.58(d, J = 8.8 Hz, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.83(dd, J = 2.5 and 8.7 Hz, 1 H); 6.91 (d, J = 2.5 Hz, 1 H); 7.05 538 (d, J= 8.7 Hz, 1 H); 7.15 (t, J = 74.5 Hz, 1 H); 9.38 (s, 1 H) 146

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-methyl-4- (trifluoromethoxy) phenyl]-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.78(dm, J = 25.3 Hz, 2 H); 2.02 to 2.13 (m, 5 H); 2.16 (s, 3 H); 2.37 (m, 1H); 2.44 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.59 to 2.81 (m, 4 H);4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.55 (d, J = 8.8 Hz,2 H); 6.58 (s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 7.01 (d,J = 9.1 Hz, 1 H); 7.10 (d, J = 2.8 Hz, 1 H); 7.12 (dd, J = 2.9 556 and9.1 Hz, 1 H); 9.40 (s, 1 H) 147

6-[5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 2-hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6- yl]-4- methyl- 1,4-benzoxazin- 3-one A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H);1.80 (dm, J = 25.3 Hz, 2 H); 2.04 (m, 2 H); 2.20 (m, 1 H); 2.29 (t, J =7.0 Hz, 2 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H);2.68 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.00 (s, 3 H); 4.47(td, J = 6.1 and 47.5 Hz, 2 H); 4.59 (s, 2 H); 4.75 (m, 1 H); 6.58 (m, 2H); 6.64 (d, J = 8.8 Hz, 2 H); 6.69 (m, 1 H); 6.77 (d, J = 8.8 Hz, 2 543H); 6.79 (m, 2 H); 6.82 (s, 1 H); 9.39 (s, 1 H) 148

6-[5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 2-hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6- yl]-4H-1,4- benzoxazin-3-one A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J =25.3 Hz, 2 H); 2.03 (m, 2 H); 2.20 (m, 3 H); 2.39 (m, 1 H); 2.48 (t, J =7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H); 2.80(d, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.51(s, 2 H); 4.75 (m, 1 H); 6.55 (s, 2 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.64(s, 1 H); 6.68 to 6.76 (m, 5 H); 9.38 (s, 1 H); 529 10.51 (s, 1 H) 149

6-(2,3- dichloro-4- ethoxy- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.31 (t, J = 7.1 Hz, 3 H); 1.68 (m, 1H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.07 (m, 2 H); 2.12 to 2.25 (m, 3 H);2.38 (m, 1 H); 2.42 to 2.56 (m, 3 H); 2.60 to 2.85 (m, 4 H); 4.08 (m, 2H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.56 (s, 2 H);6.61 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H);6.92 (d, J = 8.9 Hz, 1 H); 7.02 (d, J = 8.9 Hz, 570 1 H); 9.40 (s, 1 H)150

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[3-methyl-4- (trifluoromethoxy) phenyl]-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.13 (s, 3 H); 2.19 (m, 1 H);2.26 (m, 2 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J =3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.57 (s, 2 H);6.61 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 556 H);7.00 (dd, J = 2.3 and 8.5 Hz, 1 H); 7.17 (d, J = 8.5 Hz, 1 H); 7.25 (d,J = 2.3 Hz, 1 H); 9.40 (s, 1 H) 151

6-[3- chloro-4- (trifluoromethoxy) phenyl]-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.08 (m, 2 H); 2.19 (m, 1 H); 2.28 (t, J = 7.0Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.67(m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.77 (m, 1 H); 6.58 (s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H);6.70 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 7.19 (dd, J = 2.2 and 576 8.6Hz, 1 H); 7.34 (qd, J = 1.6 and 8.6 Hz, 1 H); 7.36 (d, J = 2.2 Hz, 1 H);9.44 (s, 1 H) 152

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(5-quinolyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.57 (m, 1 H); 1.75 (dm, J = 25.3 Hz, 2 H); 2.08 (m, 3H); 2.21 (m, 1 H); 2.31 (m, 1 H); 2.36 to 2.52 (m, 4 H); 2.58 (m, 1 H);2.69 (m, 1 H); 2.79 (m, 1 H); 2.90 (m, 1 H); 4.43 (td, J = 6.1 and 47.5Hz, 2 H); 4.61 (m, 1 H); 6.43 (d, J = 8.8 Hz, 2 H); 6.61 (m, 4 H); 6.75(d, J = 2.5 Hz, 1 H); 7.31 (d, J = 7.8 Hz, 1 H); 7.48 (dd, J = 4.5 and8.5 Hz, 1 H); 7.59 (m, 509 1 H); 7.82 (d, J = 8.5 Hz, 1 H); 8.30 (d, J =8.9 Hz, 1 H); 8.84 (dd, J = 2.0 and 4.5 Hz, 1 H); 9.42 (s, 1 H) 153

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 6-(4-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.03 (m, 2H); 2.20 (m, 1 H); 2.28 (t, J = 7.0 Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J= 7.2 Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.63 (m, 3 H); 2.80(dd, J = 6.3 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H);4.76 (m, 1 H); 6.55 (s, 2 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H);6.73 (d, J = 8.8 Hz, 2 H); 459 7.08 (d, J = 6.3 Hz, 2 H); 8032 (d, J =6.3 Hz, 2 H); 9.48 (s, 1 H) 154

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(3-pyridyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2H); 2.20 (m, 1 H); 2.29 (t, J = 7.0 Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J= 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60 to 2.72 (m, 3H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz,2 H); 4.74 (m, 1 H); 6.57 (s, 2 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.71 (s,1 H); 6.74 (d, J = 8.8 Hz, 2 459 H); 7.22 (dd, J = 5.0 and 8.3 Hz, 1 H);7.57 (td, J = 2.3 and 8.3 Hz, 1 H); 8.23 (d, J = 2.3 Hz, 1 H); 8.27 (dd,J = 2.3 and 5.0 Hz, 1 H); 9.44 (s, 1 H) 155

6-[2- chloro-6- (trifluoro- methyl)-3- pyridyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.78(dm, J = 25.3 Hz, 2 H); 2.06 to 2.31 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J= 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.64 (m, 1 H); 2.79 (m, 3 H); 4.46 (td, J= 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.59 (s, 2 H); 6.65 (d, J = 8.8Hz, 2 H); 6.73 (m, 3 H); 7.78 (d, J = 9.0 Hz, 1 H); 7.89 (d, J = 9.0 Hz,1 H); 9.49 (s, 1 H) 561 156

tert-butyl 6-[5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 2- hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6-yl]-2,3- dihydro- 1,4- benzoxazine- A 1H NMR (400 MHz, DMSO-d6, δ ppm):1.34 (s, 9 H); 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.03 (m, 2H); 2.13 to 2.27 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H);2.54 (m, 1 H); 2.65 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.71(t, J = 4.5 Hz, 2 H); 4.15 (t, J = 4.5 Hz, 2 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.75 (m, 1 H); 6.54 (m, 2 H); 6.58 to 6.65 (m, 4 H); 6.68(s, 1 H); 6.74 (d, 615 4- J = 8.8 Hz, 2 H); 7.58 carboxylate (s, 1 H);9.32 (s, 1 H) 157

6-[4- (difluoro- methylsulfanyl) phenyl]- 5-[4-[(3S)- 1-(3-fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 8,9-dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.04 (m. 2 H); 2.19 (m, 1 H); 2.27 (t, J = 7.0Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.66(m, 3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.74 (m, 1 H); 6.57 (s, 2 H); 6.60 (d, J = 8.8 Hz, 2 H);6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 7.20 (d, J = 8.6 Hz, 2 540 H);7.36 (d, J = 8.6 Hz, 2 H); 7.42 (t, J = 56.1 Hz, 1 H); 9.41 (s, 1 H) 158

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1,2,3,4- tetrahydro quinolin-7- yl)-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.66 to 1.88 (m, 5 H);2.01 (m, 2 H); 2.15 (t, J = 7.0 Hz, 2 H); 2.21 (m, 1 H); 2.39 (m, 1H);2.43 to 2.79 (m, 8 H); 2.80 (m, 1 H); 3.10 (m, 2 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.74 (m, 1 H); 5.40 (s, 1 H); 6.15 (d, J = 8.3 Hz, 1H); 6.25 (s, 1 H); 6.53 (s, 2 H); 6.55 to 6.62 (m, 3 H); 6.67 (s, 1 H);6.78 (d, J = 8.8 Hz, 2 H); 9.31 (s, 1 H) 513 159

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 6-[4-(trifluoromethoxy) phenyl]-8,9- dihydro- 7H- benzo[7] annulene-2-carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.12 (t, J = 7.0 Hz, 2 H); 2.20 (m, 1 H); 2.27(t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.55(dd, J = 3.0 and 10.5 Hz, 1 H); 2.65 (m, 1 H); 2.79 (dd, J = 6.4 and10.4 Hz, 1 H); 2.84 (t, J = 7.0 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz,2 H); 4.75 (m, 1 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.73 (d, J = 8.8 Hz, 2H); 6.87 (d, J = 8.4 Hz, 1 H); 7.19 (d, J = 8.5 570 Hz, 2 H); 7.28 (d, J= 8.5 Hz, 2 H); 7.74 (dd. J = 1.9 and 8.4 Hz, 1 H); 7.90 (d, J = 1.9 Hz,1 H); 12.84 (m, 1 H) 160

1-fluoro-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]-6-[2- fluoro-4- (trifluoromethoxy) phenyl]-8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.08 (m, 2 H); 2.03 to 2.24 (m, 3 H); 2.38 (m, 1H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.1 and 10.4 Hz, 1 H); 2.63(m, 1 H); 2.79 (m, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1H); 6.41 (d, J = 8.7 Hz, 1 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.72 (d, J =8.8 Hz, 2 H); 6.75 (t, J = 8.7 Hz, 1 H); 7.09 (dd, J = 3.0 and 8.6 Hz, 1H); 7.23 (dd, J = 3.0 and 10.3 Hz, 1 H); 7.30 (t, J = 8.6 578 Hz, 1 H);9.89 (m, 1 H) 161

1-fluoro-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]-6-[4- (trifluoro- methylsulfanyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.19 (m, 1 H); 2.30 (t, J = 7.0Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0and 10.5 Hz, 1 H); 2.64 (m, 1 H); 2.79 (m, 3 H); 4.47 (td, J = 6.1 and47.5 Hz, 2 H); 4.72 (m, 1 H); 6.41 (d, J = 8.7 Hz, 1 H); 6.60 (d, J =8.8 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.73 (t, J = 8.7 Hz, 1 H); 7.28(d, J = 8.4 Hz, 2 H); 7.50 (d, J = 8.4 Hz, 576 2 H); 9.82 (m, 1 H) 162

6-(2,4- dichloro-5- fluoro- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.08 (m, 2 H); 2.12 to 2.14 (m, 3 H); 2.38 (m, 1 H); 2.47 (t, J =7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60 to 2.86 (m, 4H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H); 6.57 (s, 2 H);6.65 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H); 6.75 (d, J = 8.8 Hz, 2 H);7.29 (d, J = 9.9 Hz, 1 H); 7.73 (d, J = 7.1 Hz, 544 1 H); 9.47 (s, 1 H)163

[5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(trifluoromethoxy) phenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-yl]dihydrogen phosphate 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.82 to 2.11 (m,5 H); 2.27 (m, 3 H); 2.70 (t, J = 7.0 Hz, 2 H); 2.80 to 3.30 (m, 6 H);4.50 (td, J = 6.1 and 47.5 Hz, 2 H); 4.83 (m, 1 H); 6.57 (d, J = 8.8 Hz,1 H); 6.61 (d, J = 8.8 Hz, 2 H); 6.70 (d, J = 8.8 Hz, 2 H); 6.90 (dd, J= 3.3 and 8.8 Hz, 1 H); 7.10 (d, J = 3.3 Hz, 1 H); 7.15 (d, J = 8.8 Hz,2 H); 7.23 (d, J = 8.8 Hz, 2 H) 622 164

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(5-methylisoxazol- 4-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.67 to 1.90 (m, 3 H); 1.81 (s, 3 H); 2.04(m, 2 H); 2.12 (m, 2 H); 2.22 (m, 1 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2Hz, 2 H); 2.58 (dd, J = 3.2 and 10.4 Hz, 1 H); 2.59 to 2.71 (m, 3 H);2.81 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2H); 4.80 (m, 1 H); 6.57 (s, 2 H); 6.70 (s, 1 H); 6.71 (d, J = 8.8 Hz, 2H); 6.80 (d, J = 8.8 Hz, 2 H); 8.39 (s, 1 H); 463 9.42 (s, 1 H) 165

6-[4- (difluoro- methoxy)-2- fluoro- phenyl]-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.19 (m, 3 H); 2.38 (m, 1 H);2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.63 (m,1 H); 2.79 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H);6.40 (d, J = 8.5 Hz, 1 H); 6.62 (d, J = 8.8 Hz, 2 H); 6.72 (d, J = 8.8Hz, 2 H); 6.74 (t, J = 8.5 Hz, 1 H); 6.89 (dd, J = 2.5 and 8.7 Hz, 1 H);6.99 (dd, J = 2.5 and 10.8 Hz, 1 560 H); 7.22 (t, J = 8.7 Hz, 1 H); 7.25(t, J = 73.8 Hz, 1 H); 9.83 (s, 1 H) 166

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(trifluoro- methylsulfonyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.07 (m, 2 H); 2.17 (m, 1 H); 2.30 to 2.40 (m, 3H); 2.46 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60to 2.72 (m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.59 (s, 2 H); 6.62 (d, J = 8.8 Hz, 2H); 6.71 (d, J = 8.8 Hz, 2 H); 6.73 (s, 1 H); 7.54 (d, J = 8.8 590 Hz, 2H); 7.90 (d, J = 8.8 Hz, 2 H); 9.55 (s, 1 H) 167

6-(3,4- dihydro- 2H-1,4- benzoxazin- 6-yl)-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol hydrochloride A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.92 to2.60 (m, 8 H); 2.62 (t, J = 7.0 Hz, 2 H); 3.11 to 4.00 (m, 8 H); 4.11(m, 2 H); 4.53 (td, J = 6.1 and 47.5 Hz, 2 H); 5.03 (m, 0.5 H); 5.09 (m,0.5 H); 6.31 (d, J = 8.5 Hz, 1 H); 6.47 (d, J = 8.5 Hz, 1 H); 6.50 to6.58 (m, 3 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.80 (d, J =8.8 Hz, 2 H); 9.38 (m, 1 H); 10.50 (m, 0.5 H); 11.03 (m, 0,5 H) 515 168

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[2-fluoro-4- (trifluoromethoxy) phenyl]- 8,9- dihydro- 7H- benzo[7]annulene-2- carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m,1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.10 to 2.23 (m, 5 H); 2.38 (m, 1 H);2.42 to 2.55 (m, 3 H); 2.62 (m, 1 H); 2.79 (dd, J = 6.3 and 10.4 Hz, 1H); 2.85 (m, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H);6.64 (d, J = 8.8 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.86 (d, J = 8.2Hz, 1 H); 7.11 (d, J = 8.6 Hz, 1 H); 7.29 (d, 588 J = 10.2 Hz, 1 H);7.35 (t, J = 8.6 Hz, 1 H); 7.73 (dd, J = 2.0 and 8.2 Hz, 1 H); 7.89 (d,J = 2.0 Hz, 1 H); 12.96 (m, 1 H) 169

5-[4-[(3S)- 1-(3- fluoropyropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-isoxazol-4- yl-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.75 to 1.90 (m, 3 H); 2.11 (m, 2 H); 2.27 (m, 3H); 2.38 to 2.55 (m, 4 H); 2.60 (t, J = 7.0 Hz, 2 H); 2.62 to 2.75 (m, 2H); 2.85 (m, 1 H); 4.49 (td, J = 6.1 and 47.5 Hz, 2 H); 4.85 (m, 1 H);6.55 (m, 2 H); 6.69 (d, J = 1.5 Hz, 1 H); 6.82 (d, J = 8.8 Hz, 2 H);6.92 (d, J = 8.8 Hz, 2 H); 7.55 (s, 1 H); 8.74 (s, 1 H); 9.43 (s, 1 H)449 170

6-(6- ethoxy-5- fluoro-3- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.30 t, J = 7.1 Hz, 3 H); 1.70 (m, 1H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.15 to 2.18 (m, 3 H);2.39 (m, 1 H); 2.48 (m, 2 H); 2.56 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.60to 2.72 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.30 (q, J = 7.1Hz, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1 H); 6.55 (s, 2H); 6.68 (d, J = 8.8 Hz, 2 H); 6.70 521 (s, 1 H); 6.78 (d, J = 8.6 Hz, 2H); 7.43 (dd, J = 2.1 and 11.9 Hz, 1 H); 7.65 (d, J = 2.1 Hz, 1 H); 9.44(s, 1 H) 171

6-fluoro-5- [5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 2- hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6-yl]pyridin- 2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.15 (t, J = 7.0 Hz, 2 H); 2.20(m, 1 H); 2.39 (m, 1 H); 2.48 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.67(m, 3 H); 2.80 (m, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1H); 6.40 (dd, J = 1.5 and 8.2 Hz, 1 H); 6.56 (m, 2 H); 6.65 (d, J = 8.8Hz, 2 H); 6.70 (s, 1 H); 7.72 (d, J = 8.8 Hz, 2 H); 7.48 (dd, 493 J =8.2 and 10.4 Hz, 1 H); 9.42 (s, 1 H); 11.11 (m, 1 H) 172

6-(6-tert- butyl-2- fluoro-4- pyridyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.01 (s, 9 H); 1.67 (m, 1 H); 1.77(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.19 (m, 1 H); 2.30 (t, J = 7.0Hz, 2 H); 2.37 (m, 1 H); 2.44 (t, J = 7.2 Hz, 2 H); 2.51 (m, 1 H); 2.60to 2.70 (m, 3 H); 2.79 (dd, J = 6.4 4.45 (td, J = 6.1 and 47.5 Hz, 2 H);4.75 (m, 1 H); 6.57 (m, 2 H); 6.67 (d, J = 8.8 Hz, 2 H); 6.71 (s, 1 H);6.73 (d, J = 8.8 Hz, 2 H); 6.78 (s, 1 H); 6.81 (s, 533 1 H); 9.51 (s, 1H) 173

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-trimethyl- silylphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 0.20 (s, 9 H); 1.69 (m, 1 H); 1.79 (dm, J= 25.3 Hz, 2 H); 2.02 (m, 2 H); 2.19 (m, 1 H); 2.26 (t, J = 7.0 Hz, 2H); 2.27 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.54 (m, 1 H); 2.62 to2.70 (m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.54 (s, 2 H); 6.60 (d, J = 8.8 Hz, 2H); 6.69 (s, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 530 7.11 (d, J = 8.0 Hz, 2H); 7.30 (d, J = 8.0 Hz, 2 H); 9.41 (s, 1 H) 174

6-(2,2- dimethylindolin- 5-yl)- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2-carboxylic acid hydrochloride B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.18(s, 6 H); 1.70 to 3.00 (m, 12 H); 2.22 (t, J = 7.0 Hz, 2 H); 2.58 (s, 2H); 2.79 (t, J = 7.0 Hz, 2 H); 4.50 (td, J = 6.1 and 47.5 Hz, 2 H); 4.89(m, 1 H); 5.51 (s, 1 H); 6.20 (d, J = 8.2 Hz, 1 H); 6.65 to 3.73 (m, 3H); 6.79 (m, 3 H); 6.82 (d, J = 8.2 Hz, 1 H); 7.70 (dd, J = 2.5 and 8.2Hz, 1 H); 7.85 (d, J = 2.5 Hz, 1 H); 12.79 (s, 1 H) 555 175

6-(1,3- benzothiazol- 5-yl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (500 MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.78 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.17 (m, 1 H); 2.34 (m, 3 H); 2.44 (t, J = 7.2 Hz,2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.71 (t, J = 7.0 Hz, 2 H); 2.76 (dd,J = 6.4 and 10.4 Hz, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m,1 H); 6.58 (m, 4 H); 6.71 (s, 1 H); 6.78 (d, J = 8.8 Hz, 2 H); 7.23 (dd,J = 1.8 and 8.4 Hz, 1 H); 7.83 (d, J = 1.8 515 Hz, 1 H); 7.92 (d, J =8.4 Hz, 1 H); 9.31 (s, 1 H); 9.41 (s, 1 H) 176

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl- 6-(2-methyl-1H- benzimidazol- 5-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3Hz, 2 H); 2.03 (m, 2 H); 2.17 (m, 1 H); 2.30 (t, J = 7.0 Hz, 2 H); 2.38(m, 1 H); 2.41 (s, 3 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.53 (m, 1 H); 2.62(m, 1 H); 2.69 (t, J = 7.0 Hz, 2 H); 2.78 (dd, J = 6.5 and 10.4 Hz, 1H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.54 (d, J = 8.8Hz, 2 H); 6.56 (s, 2 H); 6.69 (s, 1 H); 6.72 (d, 512 J = 8.8 Hz, 2 H);6.89 (dd, J = 1.7 and 8.4 Hz, 1 H); 7.10 to 7.28 (m, 2 H); 9.38 (s, 1H); 12.00 (m, 1 H) 177

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(trifluoro- methylsulfanyl) phenyl]- 8,9- dihydro- 7H- benzo[7]annulene-2- carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m,1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.11 (m, 2 H); 2.20 (m, 1 H); 2.29(t, J = 7.0 Hz, 2 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.54 (m,1 H); 2.65 (m, 1 H); 2.79 (dd, J = 6.3 and 10.4 Hz, 1 H); 2.83 (t, J =7.0 Hz, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.62(d, J = 8.8 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.83 (d, J = 8.1 Hz, 1H); 7.31 (d, J = 8.3 Hz, 2 H); 7.53 (d, J = 8.3 Hz, 2 H); 7.72 (dd, J =1.9 586 and 8.3 Hz, 1 H); 7.88 (d, J = 1.9 Hz, 1 H); 12.90 (m, 1 H) 178

6-(1,3- benzothiazol- 6-yl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.07(m, 2 H); 2.16 (m, 1 H); 2.35 (m, 3 H); 2.43 (t, J = 7.2 Hz, 2 H); 2.52(m, 1 H); 2.61 (m, 1 H); 2.71 (t, J = 7.2 Hz, 2 H); 2.76 (dd, J = 6.3and 10.5 Hz, 1 H); 4.45 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H);6.55 to 6.62 (m, 4 H); 6.71 (d, J = 2.5 Hz, 1 H); 6.73 (d, J = 8.9 Hz, 2H); 7.25 (dd, J = 1.8 and 8.5 Hz, 515 1 H); 7.82 (d, J = 8.5 Hz, 1 H);7.94 (d, J = 1.8 Hz, 1 H); 9.29 (s, 1 H); 9.31 (s, 1 H) 179

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl[oxyphenyl]- 6-(3-methylbenzo- triazol-5- yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2H); 2.08 (m, 2 H); 2.17 (m, 1 H); 2.31 to 2.53 (m, 6 H); 2.62 (m, 1 H);2.72 (t, J = 7.2 Hz, 2 H); 2.77 (dd, J = 6.1 and 10.4 Hz, 1 H); 4.20 (s,3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.57 (d, J =8.9 Hz, 2 H); 6.59 (s, 2 H); 6.71 (s, 1 H); 6.72 (d, J = 8.9 Hz, 2 H);7.05 (dd, J = 1.5 and 8.7 Hz, 1 H); 7.68 513 (s, 1 H); 7.70 (d, J = 8.7Hz, 1 H); 9.42 (s, 1 H) 180

6-[2- chloro-4- (trifluoromethoxy) phenyl]-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.78(dm, J = 25.3 Hz, 2 H); 2.03 to 2.28 (m, 5 H); 2.38 (m, 1 H); 2.45 (t, J= 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.70 to 2.81 (m, 2 H);2.99 (m, 1 H); 4.45 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m, 1 H); 6.42(d, J = 8.6 Hz, 1 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2H); 6.75 (t, J = 8.6 Hz, 1 H); 7.20 (d, J = 8.5 Hz, 1 H); 7.27 (dd, J =2.1 and 8.5 Hz, 1 H); 7.51 (d, J = 2.1 Hz, 1 H); 9.85 (s, 1 H) 594 181

6-(4-tert- butyl-2- methyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin-3- yl]oxyphenyl]- 3- yl]oxyphenyl]- 8,9- dihydro- 7H-benzo[7] annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.21 (s, 9 H);1.68 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.00 to 2.24 (m, 5 H); 2.11(s, 3 H); 2.37 (m, 1 H); 2.44 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62(m, 1 H); 2.69 to 2.80 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H);4.70 (m, 1 H); 6.53 (d, J = 8.8 Hz, 2 H); 6.56 (s, 2 H); 6.66 (d, J =8.8 Hz, 2 H); 6.70 (s, 1 H); 6.92 (dd, J = 3.3 and 8.1 Hz, 1 H); 7.04(d, J = 8.1 528 Hz, 1 H); 7.09 (s, 1 H); 9.33 (s, 1 H) 182

6-(2-fluoro- 4- methylsulfonyl- phenyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.07 (m, 2 H); 2.12 to 2.26 (m, 3 H); 2.38 (m, 1 H); 2.45 (t, J =7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.62 (m, 1 H); 2.71(t, J = 7.3 Hz, 2 H); 2.79 (dd, J = 6.1 and 10.4 Hz, 1 H); 3.22 (s, 3H); 4.47 (td, J = 6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.59 (s, 2 H);6.62 (d, J = 8.8 Hz, 2 H); 6.72 (m, 3 H); 7.47 554 (t, J = 8.0 Hz, 1 H);7.59 (dd, J = 1.8 and 8.0 Hz, 1 H); 7.62 (dd, J = 1.8 and 9.1 Hz, 1 H);9.49 (s, 1 H) 183

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 6-(3-methylisoxazol- 4-yl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.64 (s, 3 H); 1.71 (m, 1 H); 1.80 (dm, J =25.3 Hz, 2 H); 2.05 (m, 2 H); 2.15 (m, 2 H); 2.21 (m, 1 H); 2.40 (m, 1H); 2.49 (m, 2 H); 2.53 to 2.71 (m, 4 H); 2.82 (m, 1 H); 4.47 (td, J =6.0 and 47.5 Hz, 2 H); 4.80 (m, 1 H); 6.58 (m, 2 H); 6.70 (s, 1 H); 6.72(d, J = 8.9 Hz, 2 H); 6.81 (d, J = 8.9 Hz, 2 H); 8.72 (s, 1 H); 9.42 (s,1 H) 463 184

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(pentafluoro- sulfanyl) phenyl]-8,9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3Hz, 2 H); 2.05 (m, 2 H); 2.20 (m, 1 H); 2.29 (t, J = 7.0 Hz, 2 H); 2.39(m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.55 (m, 1 H); 2.60 to 2.71 (m, 3H); 2.79 (dd, J = 6.3 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz,2 H); 4.76 (m, 1 H); 6.56 (s, 2 H); 6.64 (d, J = 8.8 Hz, 2 H); 6.70 (s,1 H); 6.73 (d, J = 8.8 Hz, 2 H); 7.31 (d, J = 9.0 Hz, 584 2 H); 7.68 (d,J = 9.0 Hz, 2 H); 9.46 (s, 1 H) 185

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-morpholino phenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H);2.01 (m, 2 H); 2.15 to 2.26 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.64 (m, 3 H); 2.80 (dd,J = 6.4 and 10.4 Hz, 1 H); 3.05 (m, 4 H); 3.70 (m, 4 H); 4.47 (td, J =6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.54 (s, 2 H); 6.60 (d, J = 8.8Hz, 2 H); 6.67 (s, 1 H); 6.71 (d, J = 8.8 543 Hz, 2 H); 6.74 (d, J = 9.0Hz, 2 H); 6.98 (d, J = 9.0 Hz, 2 H); 9.31 (s, 1 H) 186

6-[4-(2,2- difluoroethoxy)- 2- fluoro- phenyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.04 (m, 2 H); 2.13 to 2.23 (m, 3 H); 2.38 (m, 1H); 2.47 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.62(m, 1 H); 2.69 (t, J = 7.0 Hz, 2 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1H); 4.29 (dt, J = 3.7 and 14.8 Hz, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz,2 H); 4.72 (m, 1 H); 6.35 (tt, J = 3.7 and 54.5 Hz, 1 H); 556 6.55 (s, 2H); 6.60 (d, J = 8.8 Hz, 2 H); 6.69 (dd, J = 2.7 and 8.7 Hz, 1 H); 6.70(s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.79 (dd, J = 2.7 and 11.9 Hz, 1H); 7.07 (t, J = 8.7 Hz, 1 H); 9.39 (s, 1 H) 187

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1-methyl- benzimidazol- 5-yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2H); 2.04 (m, 2 H); 2.17 (m, 1 H); 2.32 (t, J = 7.2 Hz, 2 H); 2.48 (m, 1H); 2.44 (t, J = 7.0 Hz, 2 H); 2.52 (m, 1 H); 2.61 (m, 1 H); 2.70 (t, J= 7.0 Hz, 2 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.78 (s, 3 H); 4.45(td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1 H); 6.54 (d, J = 8.8 Hz, 2H); 6.57 (s, 2 H); 6.70 (s, 1 H); 6.74 (d, J = 8.8 512 Hz, 2 H); 7.03(d, J = 8.4 Hz, 1 H); 7.32 (d, J = 8.4 Hz, 1 H); 7.40 (s, 1 H); 8.07 (s,1 H); 9.31 (s, 1 H) 188

6-(1,2- benzoxazol- 5-yl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.04(m, 2 H); 2.21 (m, 3 H); 2.40 (m, 1 H); 2.48 (t, J = 7.3 Hz, 2 H); 2.56(dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 3 H); 2.80 (dd, J = 6.3 and10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.78 (m, 1 H); 6.54(s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 Hz,2 H); 6.79 (d, J = 9.0 Hz, 1 499 H); 7.20 (dd, J = 2.0 and 9.0 Hz, 1 H);7.27 (d, J = 2.0 Hz, 1 H); 9.35 (s, 1 H); 11.00 (m, 1 H) 189

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1-oxidopyridin- 1-ium-4- yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.71 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2H); 2.07 (m, 2 H); 2.20 (m, 1 H); 2.25 (t, J = 7.0 Hz, 2 H); 2.40 (m, 1H); 2.48 (m, 2 H); 2.58 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.66 (t, J = 7.0Hz, 2 H); 10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.79 (m, 1H); 6.57 (s, 2 H); 6.70 (m, 3 H); 6.80 (t, J = 8.8 Hz, 2 H); 7.08 (d, J= 7.3 Hz, 2 H); 7.97 (d, J = 7.3 Hz, 2 475 H); 9.45 (s, 1 H) 190

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-pyrrolidin- 1- ylphenyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2H); 1.90 (m, 4 H); 2.00 (m, 2 H); 2.14 to 2.25 (m, 3 H); 2.39 (m, 1 H);2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.62 (m,3 H); 2.79 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.14 (m, 4 H); 4.47 (td, J =6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.32 (d, J = 8.8 Hz, 2 H); 6.52(d, J = 1.5 Hz, 2 H); 6.60 (d, J = 8.8 Hz, 527 2 H); 6.66 (t, J = 1.5Hz, 1 H); 6.74 (d, J = 8.8 Hz, 2 H); 6.92 (d, J = 8.8 Hz, 2 H); 9.39 (s,1 H) 191

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2-methyl- 1,3- benzoxazol- 5-yl)-8, 9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79 (dm, J = 25.3Hz, 2 H); 2.05 (t, J = 7.0 Hz, 2 H); 2.15 (m, 1 H); 2.30 (t, J = 7.0 Hz,2 H); 2.36 (m, 1 H); 2.45 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.53 (s,3 H); 2.62 (m, 1 H); 2.71 (t, J = 7.0 Hz, 2 H); 2.78 (dd, J = 6.4 and10.4 Hz, 1 H); 4.45 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.55(s, 2 H); 6.58 (d, J = 8.8 H z, 2 H); 6.70 (s, 1 H); 6.72 513 (d, J =8.8 H z, 2 H); 7.10 (dd, J = 1.8 and 8.5 Hz, 1 H); 7.38 (d, J = 1.8 Hz,1 H); 7.41 (d J = 8.5 Hz, 1 H); 9.38 (s, 1 H) 192

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2-methyl- 1,3- benzoxazol- 6-yl)-8, 9- dihydro- 7H- benzo[7] annulen-2-olA 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3Hz, 2 H); 2.04 (m, 2 H); 2.18 (m, 1 H); 2.30 (t, J = 7.0 Hz, 2 H); 2.37(m, 1 H); 2.44 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.54 (s, 3 H); 2.60to 2.73 (m, 3 H); 2.78 (dd, J = 6.4 and 10.4 Hz, 1 H); 4.46 (td, J = 6.1and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.55 (s, 2 H); 6.58 (d, J = 8.8 Hz, 2H); 6.70 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 513 7.08 (dd, J = 1.6 and8.3 Hz, 1 H); 7.40 (m, 2 H); 9.39 (s, 1 H) 193

6-(2,1,3- benzoxadiazol- 5-yl)- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.09 (m, 2 H); 2.19 (m, 1 H); 2.31 to 2.40 (m, 3 H); 2.45 (t, J =7.2 Hz, 2 H); 2.54 (m, 1 H); 2.60 to 2.72 (m, 3 H); 2.78 (dd, J = 6.4and 10.4 Hz, 1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.75 (m, 1 H);6.60 (s, 2 H); 6.66 (d, J = 8.8 Hz, 2 H); 6.73 (s, 1 H); 6.81 (d, J =8.8 Hz, 2 H); 7.20 (dd, J = 1.3 and 9.4 Hz, 1 H); 7.72 500 (dd, J = 1.3and 9.4 Hz, 1 H); 7.83 (t, J = 1.3 Hz, 1 H); 9.52 (s, 1 H) 194

6-(2,1,3- benzothiadiazol- 5-yl)- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.09 (m, 2 H); 2.18 (m, 1 H); 2.30 to 2.52 (m, 6 H); 2.62 (m, 1H); 2.70 to 2.80 (m, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.72 (m,1 H); 6.59 (s, 2 H); 6.61 (d, J = 8.8 Hz, 2 H); 6.72 (s, 1 H); 6.80 (d,J = 8.8 Hz, 2 H); 7.40 (dd, J = 2.0 and 9.2 Hz, 1 H); 7.80 (d, J = 9.2Hz, 1 H); 7.89 (d, J = 2.0 Hz, 1 H); 516 9.48 (s, 1 H) 195

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-[4-(oxetan-3- yl)phenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H);2.02 (m, 2 H); 2.19 (m, 1 H); 2.24 (t, J = 7.0 Hz, 2 H); 2.38 (m, 1 H);2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.2 and 10.4 Hz, 1 H); 2.65 (m,3 H); 2.79 (dd, J = 6.4 and 10.3 Hz, 1 H); 4.17 (m, 1 H); 4.47 (td, J =6.1 and 47.5 Hz. 2 H); 4.56 (dd, J = 5.9 and 6.9 Hz, 2 H); 4.72 (m, 1H); 4.89 (dd, J = 5.9 and 8.5 Hz, 2 514 H); 6.55 (s, 2 H); 6.59 (d, J =8.8 Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 Hz, 2 H); 7.12 (d, J = 8.3Hz, 2 H); 7.19 (d, J = 8.3 Hz, 2 H); 9.38 (s, 1 H) 196

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(2,2,3,3- tetrafluoro- 1,4- benzodioxin- 6-yl)-8,9- dihydro- 7H-benzo[7] annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H);1.79 (dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.20 (m, 1 H); 2.27 (t, J =7.0 Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J =3.0 and 10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.77 (m, 1H); 6.57 (s, 2 H); 6.66 (d, J = 8.8 Hz, 2 H); 6.70 (s, 1 H); 6.74 (d, J= 8.8 Hz, 2 H); 7.07 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.15 (d, 588 J = 2.0Hz, 1 H); 7.24 (d, J = 8.6 Hz, 1 H); 9.44 (s, 1 H) 197

6-(1,2- benzothiazol- 5-yl)-5- [4-[(3S)-1- (3- fluoropropyl) pyrrolidin-3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.65 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.08(m, 2 H); 2.17 (m, 1 H); 2.34 (m, 3 H); 2.44 (t, J = 7.2 Hz, 2 H); 2.52(m, 1 H); 2.61 (m, 1 H); 2.73 (m, 3 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2H); 4.70 (m, 1 H); 6.58 (m, 4 H); 6.71 (s, 1 H); 6.75 (d, J = 8.8 Hz, 2H); 7.32 (dd, J = 1.8 and 8.6 Hz, 1 H); 7.97 (d, J = 8.6 Hz, 1 H); 7.99(d, J = 1.8 Hz, 1 H); 8.97 515 (s, 1 H); 9.40 (s, 1 H) 198

6-[2,3- difluoro-4- (1- piperidyl) phenyl]-5- [4-[(3S)-1- (3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulen-2-ol A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.50 (m, 2 H); 1.60 (m,4 H); 1.69 (m, 1 H); 1.79 (dm, J = 25.3 Hz, 2 H); 2.04 (m, 2 H); 2.12 to2.25 (m, 3 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.53 (dd, J =3.0 and 10.4 Hz, 1 H); 2.60 to 2.70 (m, 3 H); 2.79 (dd, J = 6.4 and 10.4Hz, 1 H); 2.94 (m, 4 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1H); 6.56 (s, 2 H); 6.61 (d, J = 8.8 Hz, 2 H); 6.66 (s, 1 H); 6.70 (s, 1H); 6.72 (d, 577 J = 8.8 Hz, 2 H); 6.83 (dt, J = 2.0 and 8.6 Hz, 1 H);9.41 (s, 1 H) 199

6-(1,3- benzoxazol- 6-yl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.67 (m, 1 H); 1.78 (dm, J = 25.4 Hz, 2 H); 2.06(m, 2 H); 2.18 (m, 1 H); 2.30 to 2.40 (m, 3 H); 2.44 (t, J = 7.2 Hz, 2H); 2.52 (m, 1 H); 2.61 (m, 1 H); 2.70 (t, J = 7.2 Hz, 2 H); 2.78 (dd, J= 6.3 and 10.4 Hz, 1 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1H); 6.57 (d, J = 1.5 Hz, 2 H); 6.59 (d, J = 8.8 Hz, 2 H); 6.72 (d, J =8.8 Hz, 2 H); 7.14 (dd, J = 1.7 499 and 8.3 Hz, 1 H); 7.51 (d, J = 1.7Hz, 1 H); 7.55 (d, J = 8.3 Hz, 1 H); 8.62 (s, 1 H); 9.40 (s, 1 H) 200

6-(1,2- benzoxazol- 6-yl)-5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.03(m, 2 H); 2.20 (m, 3 H); 2.39 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54(dd, J = 3.0 and 10.4 Hz, 1 H); 2.64 (m, 3 H); 2.80 (dd, J = 6.4 and10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.77 (m, 1 H); 6.57(s, 2 H); 6.65 (d, J = 8.8 Hz, 2 H); 6.67 (s, 1 H); 6.70 to 6.78 (m, 4H); 7.37 (d, J = 8.3 Hz, 1 H); 499 9.43 (s, 1 H); 10.82 (m, 1 H) 201

6-[4-(1,1- difluoroethyl) phenyl]- 5-[4-[(3S)- 1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 1.91 (t, J = 18.8 Hz, 3 H); 2.04 (m, 2 H); 2.20 (m, 1 H); 2.28 (t,J = 7.0 Hz, 2 H); 2.38 (m, 1 H); 2.46 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J= 3.2 and 10.4 Hz, 1 H); 2.60 to 2.71 (m, 3 H); 2.79 (dd, J = 6.3 and10.4 Hz, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.55(s, 2 H); 6.60 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.72 (d, J = 8.8 Hz,2 522 H); 7.21 (d, J = 8.5 Hz, 2 H); 7.35 (d, J = 8.5 Hz, 2 H); 9.40 (s,1 H) 202

6-(3,6- dihydro- 2H-pyran- 4-yl)-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 to 1.89 (m, 3 H); 1.92 (m, 2 H);1.98 to 2.09 (m, 4 H); 2.25 (m, 1 H); 2.41 (m, 1 H); 2.48 (t, J = 7.2Hz, 2 H); 2.55 (t, J = 7.0 Hz, 2 H); 2.60 (dd, J = 3.0 and 10.4 Hz, 1H); 2.68 (m, 1 H); 2.83 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.53 (t, J = 5.4Hz, 2 H); 3.98 (m, 2 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.81 (m, 1H); 5.51 (m, 1 H); 6.52 (m, 2 H); 6.64 (s, 1 H); 6.76 (d, J = 8.8 Hz, 2H); 464 6.92 (d, J = 8.8 Hz, 2 H); 9.31 (s, 1 H) 203

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-tetrahydro pyran-4-yl- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): 1.40 (m, 2 H); 1.65 (m, 2 H); 1.73 to 1.89(m, 5 H); 2.05 (m, 2 H); 2.25 (m, 1 H); 2.40 to 2.72 (m, 8 H); 2.86 (dd,J = 6.4 and 10.4 Hz, 1 H); 3.14 (m, 2 H); 3.84 (m, 2 H); 4.48 (td, J =6.1 and 47.5 Hz, 2 H); 4.82 (m, 1 H); 6.42 (d, J = 8.5 Hz, 1 H); 6.48(dd, J = 2.6 and 8.5 Hz, 1 H); 6.62 (d, J = 2.6 Hz, 1 H); 6.81 (d, J =8.8 Hz, 2 H); 6.92 (d, J = 8.8 Hz, 466 2 H); 9.22 (s, 1 H) 204

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(4-hydroxy- cyclohexyl)- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR(400 MHz, DMSO-d6, δ ppm): trans diaxialisomer: 0.97 (m, 2 H); 1.38 to1.58 (m, 4 H); 1.72 to 1.89 (m, 5 H); 2.02 (m, 2 H); 2.28 (m, 2 H); 2.32(m, 1 H); 2.48 to 2.55 (m, 6 H); 2.61 (dd, J = 3.0 and 10.4 Hz, 1 H);2.69 (m, 1 H); 2.87 (dd, J = 6.4 and 10.4 Hz, 1 H); 3.32 (m, 1 H); 4.40(d, J = 4.9 Hz, 1 H); 4.49 (td, J = 6.1 and 47.5 Hz, 2 H); 4.83 (m, 1H); 6.41 (d, J = 8.6 Hz, 1 480 H); 6.48 (dd, J = 2.7 and 8.6 Hz, 1 H);6.61 (d, J = 2.7 Hz, 1 H); 6.81 (d, J = 8.9 Hz, 2 H); 6.89 (d, J = 8.9Hz, 2 H); 9.20 (s, 1 H) 205

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(3-methyl- benzimidazol- 5-yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2H); 2.06 (m, 2 H); 2.17 (m, 1 H); 2.37 (m, 3 H); 2.45 (t, J = 7.2 Hz, 2H); 2.52 (m, 1 H); 2.61 (m, 1 H); 2.71 (t, J = 7.0 Hz, 2 H); 2.77 (dd, J= 6.4 and 10.3 Hz, 1 H); 3.71 (s, 3 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2H); 4.71 (m, 1 H); 6.67 (m, 4 H); 6.70 (d, J = 1.5 Hz, 1 H); 6.72 (d, J= 8.8 Hz, 2 H) 6.91 (dd, J = 1.6 and 8.6 Hz, 1 H); 7.35 (m, 510 2 H);8.08 (s, 1 H); 9.36 (s, 1 H) 206

4-[4-[5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 2-hydroxy- 8,9- dihydro- 7H- benzo[7] annulen-6- yl]phenyl]- 1H-1,2,4-triazol-5- one A 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.05 (m, 2 H); 2.20 (m, 1 H); 2.28 (t, J = 7.0Hz, 2 H); 2.38 (m, 1 H); 2.47 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 3.0and 10.4 Hz, 1 H); 2.60 to 2.71 (m, 3 H); 2.80 (dd, J = 6.4 and 10.4 Hz,1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.56 (s, 2 H);6.62 (d, J = 8.8 Hz, 2 H); 6.69 (s, 1 H); 6.77 (d, J = 8.8 Hz, 2 H);7.22 (d, J = 8.8 Hz, 541 2 H); 7.49 (t, J = 8.8 Hz, 2 H); 8.31 (s, 1 H);9.40 (s, 1 H); 11.92 (s, 1 H) 207

6-(4,4- difluorocyclo- hexen-1- yl)-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 to 1.95 (m, 5 H); 1.98 to 2.09(m, 4 H); 2.15 (m, 2 H); 2.23 (m, 1 H); 2.37 to 2.58 (m, 7 H); 2.60 (dd,J = 3.0 and 10.4 Hz, 1 H); 2.69 (m, 1 H); 2.82 (dd, J = 6.4 and 10.4 Hz,1 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.81 (m, 1 H); 5.35 (m, 1 H);6.53 (s, 2 H); 6.63 (s, 1 H); 6.73 (d, J = 8.9 Hz, 2 H); 6.92 (d, J =8.9 Hz, 2 H); 9.31 (s, 1 H) 498 208

6-(4,4- difluorocyclo- hexyl)-5- [4-[(3S)-1- (3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulen-2-ol A1H NMR (400 MHz, DMSO-d6, δ ppm): 1.55 to 1.90 (m, 11 H); 1.95 to 2.10(m, 4 H); 2.25 (m, 1 H); 2.42 (m, 1 H); 2.46 to 2.52 (m, 3 H); 2.56 (t,J = 7.2 Hz, 2 H); 2.62 (dd, J = 3.0 and 10.3 Hz, 1 H); 2.69 (m, 1 H);2.86 (dd, J = 6.3 and 10.6 Hz, 1 H); 4.49 (td, J = 6.1 and 47.5 Hz, 2H); 4.83 (m, 1 H); 6.42 (d, J = 8.4 Hz, 1 H); 6.49 (dd, J = 2.6 and 8.4Hz, 1 H); 6.62 (d, J = 2.6 Hz, 1 H); 6.83 (d, J = 8.8 Hz, 2 H); 500 6.93(d, J = 8.8 Hz, 2 H); 9.23 (s, 1 H) 209

6-(4- chlorophenyl)- 5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2- carboxylic acid B1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz,2 H); 2.10 (m, 2 H); 2.15 to 2.28 (m, 3 H); 2.38 (m, 1 H); 2.48 (t, J =7.2 Hz, 2 H); 2.55 (dd, J = 3.2 and 10.4 Hz, 1 H); 2.65 (m, 1 H); 2.81(m, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.77 (m, 1 H); 6.65 (d, J= 8.8 Hz, 2 H); 6.73 (d, J = 8.8 Hz, 2 H); 6.81 (d, J = 8.1 Hz, 1 H);7.18 (d, J = 8.8 Hz, 2 H); 7.25 (d, J = 8.8 Hz, 2 H); 7.71 (dd, 520 J =1.9 and 8.1 Hz, 1 H); 7.87 (d, J = 1.9 Hz, 1 H); 12.05 (m, 1 H) 210

6-(2- chlorophenyl)- 5-[4- [(3S)-1-(3- fluoropropyl) pyrrolidin- 3-yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2- carboxylic acid B1H NMR (400 MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.79 (dm, J = 25.3 Hz,2 H); 2.08 to 2,24 (m, 5 H); 2.38 (m, 1 H); 2.45 (t, J = 7.2 Hz, 2 H);2.52 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.62 (m, 1 H); 2.79 (m, 1 H); 2.93(m, 2 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.71 (m, 1 H); 6.60 (d, J= 8.8 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.88 (d, J = 8.5 Hz, 1 H);7.13 to 7.25 (m, 3 H); 7.41 (d, J = 8.3 Hz, 1 H); 7.75 (dd, 520 J = 2.0and 8.5 Hz, 1 H); 7.90 (d, J = 2.0 Hz, 1 H); 12.67 (m, 1 H) 211

6-(2,4- dichlorophenyl)- 1- fluoro-5-[4- [(3S)-1-(3- fluoropropyl)pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7] annulene-2-carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m, 1 H); 1.80(dm, J = 25.3 Hz, 2 H); 2.09 to 2.27 (m, 5 H); 2.40 (m, 1 H); 2.48 (t, J= 7.2 Hz, 2 H); 2.55 (dd, J = 3.2 and 10.6 Hz, 1 H); 2.65 (m, 1 H); 2.81(m, 2 H); 3.04 (m, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.76 (m, 1H); 6.67 (d, J = 8.8 Hz, 2 H); 6.69 (d, J = 7.8 Hz, 1 H); 6.76 (d, J =8.8 Hz, 2 H); 7.21 (d, J = 8.3 Hz, 1 H); 7.30 (dd, J = 2.2 and 8.3 Hz, 1572 H); 7.60 (d, J = 2.2 Hz, 1 H); 7.65 (t, J = 7.8 Hz, 1 H) 212

6-(4- chloro-2- fluoro- phenyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulene-2- carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.69 (m,1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.08 to 2.26 (m, 5 H); 2.39 (m, 1 H);2.48 (t, J = 7.2 Hz, 2 H); 2.54 (dd, J = 2.8 and 10.4 Hz, 1 H); 2.64 (m,1 H); 2.80 (dd, J = 6.4 and 10.4 Hz, 1 H); 2.87 (t, J = 7.2 Hz, 2 H);4.48 (td, J = 6.2 and 47.6 Hz, 2 H); 4.76 (m, 1 H); 6.67 (d, J = 8.8 Hz,3 H); 6.77 (d, J = 8.8 Hz, 2 H); 7.18 (dd, J = 2.1 and 8.3 Hz, 1 H);7.24 (t, J = 8.3 Hz, 556 1 H); 7.32 (dd, J = 2.1 and 9.8 Hz, 1 H); 7.60(t, J = 8.0 Hz, 1 H); 12.40 (m, 1 H) 213

6-(2- chloro-4- fluoro- phenyl)-1- fluoro-5-[4- [(3S)-1-(3-fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 8,9- dihydro- 7H- benzo[7]annulene-2- carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m,1 H); 1.79 (dm, J = 25.4 Hz, 2 H); 2.04 to 2.25 (m, 5 H); 2.38 (m, 1 H);2.46 (t, J = 7.2 Hz, 2 H); 2.52 (m, 1 H); 2.63 (m, 1 H); 2.79 (m, 2 H);3.00 (m, 1 H); 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.51(d, J = 8.2 Hz, 1 H); 6.62 (d, J = 8.9 Hz, 2 H); 6.73 (d, J = 8.9 Hz, 2H); 7.08 (dt, J = 2.7 and 8.7 Hz, 1 H); 7.21 (dt, J = 6.4 and 8.7 Hz, 1H); 7.32 (t, J = 8.2 Hz, 556 1 H); 7.40 (dd, J = 2.7 and 8.7 Hz, 1 H);12.00 (m, 1 H) 214

9-(4-{[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxy}phenyl)- 8-phenyl- 6,70 dihydro- 5H- benzo[7] annulen-3-ol A 1H NMR (400 MHz,DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2 H); 2.04 (m, 2H); 2.19 (m, 1 H); 2.27 (t, J = 7.0 Hz, 2 H); 2.40 (m, 1 H); 2.48 (m, 2H); 2.55 (m, 1 H); 2.60 to 2.71 (m, 3 H); 2.80 (m, 1 H); 4.48 (td, J =6.1 and 47.5 Hz, 2 H); 4.73 (m, 1 H); 6.56 (m, 2 H); 6.59 (d, J = 8.8Hz, 2 H); 6.69 (s, 1 H); 6.71 (d, J = 8.8 Hz, 2 H); 7.05 to 7.19 (m, 5H); 9.37 (s, 1 H) 457 215

5-[4-[(3S)- 1-(3- fluoropropyl) pyrrolidin- 3- yl]oxyphenyl]- 6-(1H-indazol-5- yl)-8,9- dihydro- 7H- benzo[7] annulen-2-ol A 1H NMR (400MHz, DMSO-d6, δ ppm): 1.66 (m, 1 H); 1.78 (dm, J = 25.3 Hz, 2 H); 2.06(m, 2 H); 2.17 (m, 1 H); 2.29 to 2.40 (m, 3 H); 2.43 (t, J = 7.2 Hz, 2H); 2.53 (m, 1 H); 2.61 (m, 1 H); 2.70 (t, J = 7.0 Hz, 2 H); 2.77 (dd, J= 6.4 and 10.4 Hz, 1 H; 4.47 (td, J = 6.1 and 47.5 Hz, 2 H); 4.70 (m, 1H); 6.54 (d, J = 8.8 Hz, 2 H); 6.56 (s, 2 H); 6.70 (s, 1 H); 6.72 (d, J= 8.8 Hz, 2 H); 7.09 (d, 498 J = 8.7 Hz, 1 H); 7.30 (d, J = 8.7 Hz, 1H); 7.52 (s, 1 H); 7.91 (s, 1 H); 9.35 (s, 1 H); 12.90 (s, 1 H) 216

6-(2- Chloro-3- fluoro- phenyl)-5- {4-[(S)-1- (3-fluoro- propyl)-pyrrolidin- 3-yloxy]- phenyl}- 8,9- dihydro- 7H- benzocyclo- heptene- 2-carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.68 (m, 1 H); 1.79(dm, J = 25.3 Hz, 2 H); 2.10 to 2.25 (m, 5 H); 2.18 (m, 1 H); 2.46 (t, J= 7.2 Hz, 2 H); 2.53 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.63 (m, 1 H); 2.79(m, 1 H); 2.93 (t, J = 7.0 Hz, 2 H); 4.46 (td, J = 6.1 and 47.5 Hz, 2H); 4.73 (m, 1 H); 6.63 (d, J = 8.8 Hz, 2 H); 6.73 (d, J = 8.8 Hz, 2 H);6.89 (d, J = 8.1 Hz, 1 H); 7.05 (m, 1 H); 7.24 (m, 2 H); 7.77 (dd, J =2.0 and 8.1 Hz, 1 H); 7.91 (d, J = 2.0 538 Hz, 1 H); 12.60 (m, 1 H) 217

5-{4-[(S)-1- (3-Fluoro- propyl)- pyrrolidin- 3-yloxy]- phenyl}-6-phenyl- 8,9- dihydro- 7H- benzocyclo- heptene- 2- carboxylic acid B 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H); 1.80 (dm, J = 25.3 Hz, 2H); 2.11 (m, 2 H); 2.20 (m, 1 H); 2.27 (t, J = 7.0 Hz, 2 H); 2.41 (m, 1H); 2.48 (m, 2 H); 2.58 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.67 (m, 1 H);2.83 (m, 3 H); 4.48 (td, J = 6.1 and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.62(d, J = 8.8 Hz, 2 H); 6.72 (d, J = 8.8 Hz, 2 H); 6.89 (d, J = 8.1 Hz, 1H); 7.10 to 7.25 (m, 5 H); 7.73 (dd, J = 2.0 and 8.1 Hz, 1 H); 7.89 (d,J = 2.0 Hz, 486 1 H); 12.84 (m, 1 H) 218

6- Benzooxazol- 5-yl-5- {4-[(S)-1- (3-fluoro- propyl)- pyrrolidin-3-yloxy]- phenyl}- 8,9- dihydro- 7H- benzo- cyclo- heptene- 2-carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.90 to 2.08 (m, 4H); 2.14 (m, 2 H); 2.32 (t, J = 7.0 Hz, 2 H); 2.90 (t, J = 7.0 Hz, 2 H);3.00 to 3.40 (m, 6 H); 4.51 (td, J = 6.1 and 47.5 Hz, 2 H); 4.98 (m, 1H); 6.70 (d, J = 8.8 Hz, 2 H); 6.81 (d, J = 8.8 Hz, 2 H); 6.88 (d, J =8.1 Hz, 1 H); 7.25 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.60 (m, 2 H); 7.77(dd, J = 2.0 and 8.1 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.69 (s, 1 H);9.92 (m, 1 H); 12.85 (m, 1 H) 527 219

6-[4-(1,1- Difluoro- ethyl)- phenyl]-5- {4-[(S)-1- (3-fluoro- propyl)-pyrrolidin- 3-yloxy]- phenyl}- 8,9- dihydro- 7H- benzo- cyclo- heptene-2- carboxylic acid B 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.70 (m, 1 H);1.79 (dm, J = 25.3 Hz, 2 H); 1.92 (t, J = 19.0 Hz, 3 H); 2.11 (m, 2 H);2.20 (m, 1 H); 2.28 (t, J = 7.0 Hz, 2 H); 2.39 (m, 1 H; 2.46 (t, J = 7.2Hz, 2 H); 2.55 (dd, J = 3.0 and 10.4 Hz, 1 H); 2.65 (m, 1 H); 2.79 (dd,J = 6.4 and 10.4 Hz, 1 H); 2.84 (t, J = 7,0 Hz, 2 H); 4.47 (td, J = 6.1and 47.5 Hz, 2 H); 4.74 (m, 1 H); 6.64 (d, J = 8.8 Hz, 2 H); 6.86 (d, J= 8.1 Hz, 1 H); 7.27 (d, J = 8.8 550 Hz, 2 H); 7.39 (d, J = 8.8 Hz, 2H); 7.73 (dd, J = 2.0 and 8.1 Hz, 1 H); 7.90 (d, J = 2.0 Hz, 1 H); 12.48(m, 1 H)

The examples which follow describe the preparation of some compounds offormula (I). The numbers of the compounds exemplified below match thosegiven in the Table 1 above. All reactions are performed under inertatmosphere, unless otherwise stated.

INTERMEDIATES Compound (c). Tert-butyl(3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1-carboxylate

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon(R)-1-N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed byN,N,N′,N′-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clearreaction mixture turned orange and triphenylphosphine (143.41 g, 546.77mmol) was added. The reaction mixture was stirred at room temperaturefor 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed(Ph₃P═O). The reaction mixture was poured in water (1.5 L) and extractedwith ethyl acetate (AcOEt) (3×1.5 L). Gathered organic phases were driedover magnesium sulfate (MgSO₄), filtered and concentrated under reducedpressure. The residue was taken up into diisopropylether (1.5 L) and thesolid formed (Ph₃P═O) was filtered. The solvent was concentrated underreduced pressure and the residue purified by column chromatographyeluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g(100%) of tert-butyl(3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate(c) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s, 12H); 1.39 (s, 9H); 2.05 (m,1H); 2.14 (m, 1H); 3.37 (3H); 3.55 (m, 1H); 5.05 (s, 1H); 6.94 (d, J=8.4Hz, 2H); 7.61 (d, J=8.4 Hz, 2H)

Compound (d).(3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine,hydrochloride

To a solution of (S)-tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate(c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCl 4N indioxane (250 ml).

After 1.5 hours, the reaction mixture was concentrated under reducedpressure and the residue was taken up into Et₂O with stirring to give asolid which then was filtered and dried under vacuum to give compound(d) 61.8 g (95%) as a white powder.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s, 12H); 2.10 (m, 1H); 2.21 (m,1H); 3.31 (3H); 3.48 (m, 1H); 5.19 (m, 1H); 6.97 (d, J=8.4 Hz, 2H); 7.63(d, J=8.4 Hz, 2H); 9.48 (s, 1H); 9.71 (s, 1H).

LC/MS (m/z, MH⁺): 290

Reagent (1).(3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

To a suspension of(S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidinehydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was addedK₂CO₃ (21.22 g, 153.54 mmol) and 1-iodo-3-fluoropropane (12.15 g, 61.42mmol), under argon. The reaction mixture was stirred at 40° C. for 24hours. After cooling to room temperature, the reaction mixture wasfiltered and washed with acetonitrile. The filtrate was concentratedunder reduced pressure and the residue was taken up in DCM and the solidformed was filtered and washed with DCM. The filtrate was concentratedto give reagent (1) 21.5 g (100%) as a yellow foam.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s, 12H); 1.77 (m, 2H); 1.84 (m,1H); 2.27 (m, 1H); 2.41 (m, 1H); 2.49 (2H); 2.62 (dd, J=2.6 and 10.4 Hz,1H); 2.69 (m, 1H); 2.83 (dd, J=6.2 and 10.4 Hz, 1H); 4.47 (td, J=6.2 and47 Hz, 2H); 4.99 (m, 1H); 6.77 (d, J=8.4 Hz, 2H); 7.58 (d, J=8.4 Hz,2H).

LC/MS (m/z, MH⁺): 350

Intermediate (A1). 9-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate

To a solution of 3-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(2.42 g, 13.73 mmol), in acetone (100 ml), was added K₂CO₃ (1.90 g,13.73 mmol) and pivaloyl chloride (1.69 ml, 13.73 mmol). The reactionmixture was stirred at room temperature for 18 hours, then was filteredand concentrated under reduced pressure. The residue was purified byflash chromatography eluting with a gradient of heptane in AcOEt (100/0to 85/15, v/v) to give 2.62 g (73%) of9-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate(A1) which was used as such in the next step.

Intermediate (B1).9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate

To a solution of 9-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (A1) (2.6 g, 10 mmol) in DCM (100 ml) was addedunder argon pyridine (1.26 ml, 14.98 mmol) and trifluoromethanesulfonicanhydride (3.39 ml, 19.97 mmol) dropwise. The reaction mixture wasstirred at room temperature for 16 hours and ice (200 g) and DCM (200ml) were added. The phases were separated, the aqueous phase was washedwith DCM and the gathered organic phases were dried over MgSO₄, filteredand evaporated under reduced pressure. The residue was purified by flashchromatography eluting with a gradient of heptane in AcOEt (100/0 to90/10, v/v) to give 3.65 g (93%) of9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (B1) as an orange oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.30 (s, 9H); 1.98 (m, 2H); 2.26 (m,2H); 2.72 (m, 2H); 6.46 (t, J=6.2 Hz, 1H); 7.10 to 7.14 (m, 2H); 7.38(m, 1H)

Intermediate (C1).9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate

To a solution of9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (B1) (600 mg, 1.53 mmol) and(S)-1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine(1) (534 mg, 1.53 mmol) in dioxane (24 ml) and water (6 ml), Cs₂CO₃(1.05 g, 3.21 mmol) was added under argon, followed by Pd(dppf)Cl₂(124.87 mg, 0.15 mmol). The reaction mixture was stirred for 20 minutesat 60° C. After cooling to room temperature, water (40 ml) and DCM (200ml) were added. After decantation, the organic phase was dried overMgSO₄, then was filtered and concentrated under reduced pressure. Theobtained residue was purified by column chromatography eluting with agradient of MeOH in DCM (0 to 4%; V/V) to give 0.7 g (98%) of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (C1).

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.24 (s, 9H); 1.70 to 1.92 (m, 5H);2.11 (m, 2H); 2.26 (m, 1H); 2.42 (m, 1H); 2.48 (t, J=7.2 Hz, 2H); 2.52to 2.74 (m, 4H); 2.85 (dd, J=6.2 and 10.4 Hz, 1H); 4.49 (td, J=6.1 and47.5 Hz, 2H); 4.85 (m, 1H); 6.39 (t, J=7.4 Hz, 1H); 6.59 (d, J=2.6 Hz,1H); 6.84 (d, J=8.8 Hz, 2H); 6.97 (dd, J=2.6 and 8.2 Hz, 1H); 7.11 (d,J=8.8 Hz, 2H); 7.35 (d, J=8.2 Hz, 1H)

Intermediate (D1).8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-yl-2,2-dimethylpropanoate

To a solution of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (C1) (700 mg, 1.50 mmol) in THF (30 ml), wasadded pyridinium tribromide (481 mg, 1.50 mmol). The reaction mixturewas stirred for 2.5 hours at room temperature. Water (20 ml) was addedand pH was adjusted to 7 with concentrated solution of NaHCO₃. DCM (60ml) was added. The aqueous phase was washed with DCM, 3 times and thegathered organic phases were dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) togive 0.667 g (82%) of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (D1).

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.21 (s, 9H); 1.71 to 1.91 (m, 3H);2.18 to 2.33 (m, 3H); 2.42 (m, 1H); 2.48 (t, J=7.2 Hz, 2H); 2.50 (m,2H); 2.62 (dd, J=3.0 and 10.4 Hz, 1H); 2.65 to 2.77 (m, 3H); 2.86 (dd,J=6.2 and 10.4 Hz, 1H); 4.49 (td, J=6.1 and 47.5 Hz, 2H); 4.87 (m, 1H);6.44 (d, J=2.6 Hz, 1H); 6.88 (d, J=8.8 Hz, 2H); 6.97 (dd, J=2.6 and 8.2Hz, 1H); 7.10 (d, J=8.8 Hz, 2H); 7.34 (d, J=8.2 Hz, 1H)

Intermediate (D2).8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-yl-2,2-dimethylpropanoate(D1) (665 mg, 1.22 mmol) in methanol (30 ml), was added NaOH (5N, 2 ml,10.00 mmol). The reaction mixture was stirred 15 minutes at roomtemperature and 2 ml of HCl 5N was added. The solvent was removed underreduced pressure. The residue was taken up into AcOEt. The phases wereseparated and the aqueous phase was washed with AcOEt. The organicphases were combined and dried over MgSO₄, then were filtered andconcentrated under reduced pressure and the residue was purified bycolumn chromatography eluting with a gradient of MeOH in DCM (0 to 3%;V/V) to give 0.4 g (72%) of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol(D2).

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.71 to 1.89 (m, 3H); 2.14 (m, 2H);2.28 (m, 1H); 2.38 to 2.55 (m, 5H); 2.58 to 2.72 (m, 4H); 2.87 (dd,J=6.4 and 10.4 Hz, 1H); 4.49 (td, J=6.1 and 47.5 Hz, 2H); 4.85 (m, 1H);6.20 (d, J=2.7 Hz, 1H); 6.60 (dd, J=2.7 and 8.2 Hz, 1H); 6.87 (d, J=8.8Hz, 2H); 7.18 (d, J=8.8 Hz, 3H); 9.11 (s, 1H)

LC/MS (m/z, MH⁺): 460

Intermediate (A2). 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

To a solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(15 g, 78.85 mmol) in toluene (400 ml) was added AlCl₃ (25 g, 187.49mmol). The reaction mixture was stirred at 91° C. (bath temperature) for45 minutes, cooled to room temperature and poured onto ice (900 g). Theslurry was stirred for 20 minutes and the solid formed was filtered,washed with water (200 ml), and diisopropyl ether (200 ml), and then wasdried to give 14.1 g (100%) of2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A2) as a beigepowder.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 10.1 (s, 1H); 7.53 (d, 1H); 6.68 (dd,1H); 6.62 (d, 1H); 2.84 (t, 2H); 2.52 (t, 2H); 1.65 (q, 2H); 1.55 (q,2H).

LC/MS (m/z, MH⁺): 177

Intermediate (A3). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate

To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(A2) (1.52 g, 8.63 mmol), in acetone (60 ml), was added K₂CO₃ (1.19 g,8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reactionmixture was stirred at room temperature for 16 hours, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography eluting with a gradient of heptane in AcOEt (100/0 to85/15, v/v) to give 1.55 g (69%) of5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate(A3) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1H); 7.10-7.04 (m, 2H); 2.95(t, 2H); 2.68 (t, 2H); 1.85-1.65 (m, 4H).

LC/MS (m/z, MH⁺): 261

Intermediate (B2).9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate (A3) (15 g, 57.62 mmol) in DCM (500 ml) was addeddropwise under argon pyridine (7.28 ml, 86.43 mmol) andtrifluoromethanesulfonic anhydride (19.58 ml, 115.24 mmol). The reactionmixture was stirred at room temperature for 2 hours and ice (200 g) wasadded. The phases were separated, the aqueous phase was washed with DCMand the gathered organic phases were dried over MgSO₄, filtered andevaporated under reduced pressure to give 22 g (97%) of9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (B2) as a white solid.

LC/MS (m/z, MH⁻): 391

Intermediate (C2).9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate

To a solution of9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(B2) (22 g, 56.07 mmol) and(3S)-1-(3-fluoropropyl)-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine(1) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) wereadded under argon Pd(dppf)C₂ (2.75 g, 3.36 mmol) and Cs₂CO₃ (36.57 g,112.13 mmol). The reaction mixture was stirred for 1 hour at roomtemperature and was partitioned between water and DCM. The aqueous phasewas washed with DCM and the gathered organic phases dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with a gradient of MeOH in DCM(0 to 5%; V/V) to give 31 g (100%) of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(C2).

LC/MS (m/z, MH⁺): 466

Intermediate (D3).8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate

To a solution of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(C2) (11 g, 22.44 mmol) in THF (250 ml), was added pyridinium tribromide(7.98 g, 22.44 mmol). The reaction mixture was stirred for 1 hour atroom temperature and 100 ml of water was added followed by a saturatedsolution of sodium bicarbonate (NaHCO₃) until pH 7. The aqueous phasewas washed with DCM, 3 times and the gathered organic phases were driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with a gradient ofMeOH in DCM (0 to 4%; V/V) to give 9.2 g (75%) of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(D3).

LC/MS (m/z, MH⁺): 545

Intermediate (D4).8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(D3) (9.2 g, 16.90 mmol) in MeOH (250 ml), was added NaOH (2N, 50 ml,100 mmol). The reaction mixture was stirred 15 minutes at roomtemperature and 22 ml of aqueous HCl 5N was added. The solvent wasremoved under reduced pressure and the residue was taken up into DCM.The phases were separated and the aqueous phase was washed with DCM andAcOEt. The organic phase was dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0 to 05%; V/V) togive 6.03 g (78%) of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4).

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.71 to 1.89 (m, 3H); 2.19 (m, 2H);2.28 (m, 1H); 2.39 to 2.52 (m, 5H); 2.59 to 2.72 (m, 4H); 2.87 (dd,J=6.4 and 10.4 Hz, 1H); 4.49 (td, J=6.1 and 47.5 Hz, 2H); 4.83 (m, 1H);6.52 (s, 2H); 6.68 (s, 1H); 6.83 (d, J=8.8 Hz, 2H); 7.07 (d, J=8.8 Hz,2H); 9.50 (s, 1H)

LC/MS (m/z, MH⁺): 461

Intermediate (A4).5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate

To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(A2) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 113.505mmol), cooled at 5° C. under argon, was added dropwisetrifluoromethanesulfonic anhydride (20.22 ml, 123.29 mmol) while keepingtemperature between 10 and 20° C. The reaction mixture was stirred for 1hour at 5° C. then at room temperature for 1 hour.

Then, ice (200 g) was added and the slurry partitioned between water andDCM. The organic phase was washed with aqueous NaHCO₃ solution, driedover MgSO₄, filtered off and concentrated under reduced pressure. Theresidue was purified by flash chromatography eluting with a gradient ofheptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate (A4) as an orange oil.

LC/MS (m/z, MH⁺): 309

Intermediate (A5). Methyl5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate (A4) (5.03 g, 16.32 mmol) in DMF (24 ml) andMeOH (12 ml), were added Pd(dppf)Cl₂ (754 mg, 0.98 mmol) anddiisopropylethylamine (6 ml). The black suspension was carbonylated inan autoclave at 70° C. under 5 bars of CO for 2.5 hours. The reactionmixture was filtered, then the filtrate was partially concentrated underreduced pressure, and the residue, was partitioned between AcOEt andwater. The organic phase was washed with water (2×75 ml) and aqueous HCl0.5 N, dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography eluting with a gradient ofheptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (A5) as acolorless oil.

LC/MS (m/z, MH⁺): 219

Intermediate (B3). methyl9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (A5) (18.19g, 83.34 mmol) in DCM (500 ml) and anhydrous pyridine (11 ml, 130.56mmol), cooled at 5° C. under argon, was added dropwisetrifluoromethanesulfonic anhydride (30 ml, 176.54 mmol). The reactionmixture, a thick suspension, was stirred at room temperature for 24hours, then ice was added and partitioned between water and DCM.

The organic phase was dried over MgSO₄, filtered off and concentratedunder reduced pressure to give 29 g (100%) of methyl9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(B3) as a yellow gum.

LC/MS (m/z, MH⁺): 351

Intermediate (C3). methyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(B3) (29 g, 82.9 mmol),(3S)-1-(3-fluoropropyl)-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine(1) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)Cl₂under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs₂CO₃ 1.5 Maqueous solution (111.12 ml, 166.68 mmol). The reaction mixture wasstirred at 60° C. for 1 hour.

After cooling to room temperature, the reaction mixture was poured intoa mixture of water (500 ml) and AcOEt (400 ml). The organic phase waswashed with brine, dried over MgSO₄, filtered on celite and concentratedunder reduced pressure. The residue was purified by flash chromatographyeluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g(65%) of methyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(C3) as a brown gum.

LC/MS (m/z, MH⁺): 424

Intermediate (D5). Methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide

To a solution of methyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(C3) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argonpyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture wasstirred for 1 hour at room temperature. Water (200 ml) was added,organic phase was then dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by flash chromatography eluting witha gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) ofmethyl8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide (D5) as a yellow meringue.

LC/MS (m/z, MH⁺): 502

Intermediate (C4).9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

To a solution under argon of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(C2) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml,115.00 mmol). The reaction mixture was stirred for 2 hours at roomtemperature. pH was then adjusted to 7 by addition of 6N aqueous HClsolution. The MeOH was concentrated under reduced pressure, then DCM wasadded. The organic phase was dried over MgSO₄, and concentrated underreduced pressure. The residue was purified by flash chromatographyeluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 18.8 g(93%) of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(C4) as a beige solid.

LC/MS (m/z, MH⁺): 382

Intermediate (C5).9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate

To a solution of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(C4) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81.00mmol), cooled to 5° C. (ice bath), was added dropwisetrifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon,and the reaction temperature was maintained <15° C. The ice bath wasremoved, and the brown suspension was stirred at room temperature for 2hours. Ice (200 g) and DCM (200 ml) were added and the phases separated.The organic phase was dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by flash chromatography eluting witha gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1%) of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate (C5) as a brown oil.

LC/MS (m/z, MH⁺): 514

Intermediate (C3). Methyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate (C5) (10.1 g, 19.67 mmol) in DMF (66 ml) andMeOH (33 ml), were added Pd(dppf)Cl₂ (909 mg, 1.18 mmol) anddiisopropylethylamine (7.21 ml). The black suspension was carbonylatedin an autoclave at 70° C. under 5 bars of CO for 5 hours. The reactionmixture was filtered, then the filtrate was partially concentrated underreduced pressure. The residue was partitioned between AcOEt and water.The organic phase was washed with water (2×100 ml), dried over MgSO₄,and concentrated under reduced pressure. The residue was purified byflash chromatography eluting with a gradient of DCM/MeOH from 100/0 to95/05 to give 7.13 g (86%) of methyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(C3) as a brown gum.

LC/MS (m/z, MH⁺): 424

Intermediate (A6).1-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

Step 1. Ethyl 5-(2-fluoro-3-methoxyphenyl)pent-4-enoate

To a solution of [3-(ethoxycarbonyl)propyl]triphenylphosphonium bromide(30 g, 65.5 mmol) in THF (300 ml) cooled at −78° C., was added potassiumbis(trimethylsilyl)amide (16 g, 80.45 mmol) in 5 minutes. The orangesuspension was stirred 1 hour at −78° C., and2-fluoro-3-methoxybenzaldehyde (10 g, 65 mmol) was added. The reactionmixture was allowed to reach room temperature overnight under stirring.The solvent was concentrated under reduced pressure, the residue takenup in AcOEt (300 ml), washed twice with sodium bisulfite, 10% (w/v)aqueous solution (50 ml).

The organic phase was dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography eluting with a mixture of AcOEt/cyclohexane 10/90 to give9 g (55%) of (E)-ethyl 5-(2-fluoro-3-methoxyphenyl)pent-4-enoate as ayellow oil.

LC/MS (m/z, MH⁺): 253 mixture of E/Z isomers 69/31%

Step 2. Ethyl 5-(2-fluoro-3-methoxyphenyl)pentanoate

To a solution of (E)-ethyl 5-(2-fluoro-3-methoxyphenyl)pent-4-enoate (9g, 35.67 mmol) in ethanol (100 ml), was added Pd/C 10% (100 mg). Theblack suspension was hydrogenated in an autoclave, at room temperatureunder 10 bars of hydrogen during 24 hours. The slurry was filtered thenthe filtrate was concentrated under reduced pressure to give 8.9 g (98%)of ethyl 5-(2-fluoro-3-ethoxyphenyl)pentanoate as a colorless oil.

LC/MS (m/z, MH⁺): 255

Step 3. 5-(2-fluoro-3-methoxyphenyl)pentanoic acid

To a solution of ethyl 5-(2-fluoro-3-methoxyphenyl)pentanoate (8.9 g,35.00 mmol) in ethanol (60 ml), were added water (12 ml) and NaOH 32% (6ml, 72 mmol). The white suspension was then stirred for 2 hours at 50°C. After cooling to room temperature, 100 g of ice were added and thereaction mixture was acidified with aqueous HCl to pH 3. The solidobtained was filtered off and dried to give 7.9 g (100%) of5-(2-fluoro-3-methoxyphenyl)pentanoic acid as a white solid.

LC/MS (m/z, MH⁻): 225

Step 4. 1-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(A6)

5-(2-fluoro-3-methoxyphenyl)pentanoic acid (4.8 g, 21.22 mmol) was addedto trifluoromethane sulfonic acid (19 ml, 212 mmol) cooled at 5° C. Thebrown solution was stirred at 5° C. during 1 hour. Ice (100 g) and AcOEt(100 ml) were added, followed by an aqueous solution of NaHCO₃ until pHwas 7. The organic phase was dried over MgSO₄, filtered off andconcentrated under reduced pressure to give 4.4 g (99%) of1-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A6) as abrown oil.

LC/MS (m/z, MH⁺): 209

Intermediate (A7).1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

To a solution of1-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A6) (6.2g, 29.8 mmol) in toluene (100 ml) was added AlCl₃ (4.76 g, 35.7 mmol).The brown suspension was stirred for 1 hour at 90° C. After cooling toroom temperature, the hot mixture was poured into 900 g of iced water.The solid obtained was filtered off, washed with water, aqueous HCl 0.1N and dried to give 5.3 g (92%) of1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A7) as abeige solid.

LC/MS (m/z, MH⁺): 195

Intermediate (A8).1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl2,2-dimethylpropanoate

To a solution of1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A7) (5.3g, 27.3 mmol) in acetone (150 ml) were added K₂CO₃ (3.77 g, 27.29 mmol)and pivaloyl chloride (2.29 g/3.36 ml, 27.3 mmol). The orange suspensionwas stirred for 2 hours at room temperature. The solids were filteredoff and then washed with acetone (10 ml). The filtrate was concentratedunder reduced pressure. AcOEt (100 ml) and water were added to theresidue obtained. The organic phase was dried over MgSO₄, filtered offand concentrated under reduced pressure to give 7.2 g (95%) of1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl-2,2-dimethylpropanoate(A8) as a beige solid.

LC/MS (m/z, MH⁺): 279

Intermediate (B4).4-fluoro-9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate

To a solution of1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl-2,2-dimethylpropanoate(A8) (2.05 g, 7.37 mmol) in DCM (50 ml) was added under argon pyridine(0.93 ml, 11.05 mmol) and trifluoromethanesulfonic anhydride (2.5 ml,14.73 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 2 hours and ice (100 g) was added. The phases wereseparated, the aqueous phase was washed with DCM and the gatheredorganic phases were dried over MgSO₄, filtered and evaporated underpressure. The residue was purified by flash chromatography eluting withDCM to give 2.5 g (83%) of4-fluoro-9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(B4) as a yellow oil.

LC/MS (m/z, MH⁺): 411

Intermediate (C6).4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate

To a solution of4-fluoro-9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(B4) (700 mg, 1.71 mmol) and(S)-1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine(1) (595.72 mg, 1.71 mmol) in dioxane (10 ml) and water (0.5 ml), wereadded Cs₂CO₃ (1.17 g, 3.58 mmol) and Pd(dppf)Cl₂ (139 mg, 0.171 mmol).The reaction mixture was stirred for 1 hour at room temperature andpartitioned between water and AcOEt. The aqueous phase was washed withAcOEt and the gathered organic phases were dried over MgSO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with DCM/MeOH/NH₄OH 28% 93/6.3/0.07 togive 0.55 g (67%) of(4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (C6).

LC/MS (m/z, MH⁺): 484

Intermediate (D6).(8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate

To a solution of(4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(C6) (550 mg, 1.14 mmol) in THF (30 ml), was added pyridinium tribromide(404 mg, 1.14 mmol). The reaction mixture was stirred for 1 hour at roomtemperature. A solution of ammonium dihydrogen phosphate (NH₄H₂PO₄) andAcOEt was added. The aqueous phase was washed with AcOEt and thegathered organic phase dried over MgSO₄ and filtered. The organic phasewas concentrated under reduced pressure to give 0.63 g (98%) of8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(D6).

LC/MS (m/z, MH⁺): 562

Intermediate (D7).8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

To a solution of8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (D6) (640 mg, 1.14 mmol) in MeOH (15 ml), wasadded NaOH (2N, 2.84 ml, 5.69 mmol). The reaction mixture was stirredfor 1 hour at room temperature and 2 ml of aqueous HCl 2N was added andthe pH was adjusted to 5 with a solution of aqueous ammonium chloride(NH₄Cl). The solvent was removed under reduced pressure and the residuetaken up into AcOEt. The phases were separated and the aqueous phase waswashed with AcOEt. The organic phases were combined and dried overMgSO₄, filtered and concentrated under reduced pressure.

The residue was purified by column chromatography eluting with DCM/MeOH:95/05 to give 0.47 g (86%) of8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D7) as a grey solid.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.71 to 2.00 (m, 3H); 2.20 (m, 2H);2.25 to 3.15 (m, 11H); 4.50 (td, J=6.1 and 47.5 Hz, 2H); 4.92 (m, 1H);6.38 (d, J=8.5 Hz, 1H); 6.71 (t, J=8.5 Hz, 1H); 6.88 (d, J=8.8 Hz, 2H);7.10 (d, J=8.8 Hz, 2H); 9.93 (s, 1H); 10.03 (m, 1H)

LC/MS (m/z, MH⁺): 478

Intermediate (A9).1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethane sulfonate

To a solution of1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A7) (5.5g, 28.32 mmol), in DCM (35 ml) and lutidine (6.66 ml, 56.64 mmol),cooled at 5° C. under argon, was added dropwise trifluoromethanesulfonicanhydride (9.30 ml, 56.64 mmol) while keeping temperature between 10 and20° C. The reaction mixture was stirred at 5° C. for 1 hour and then atroom temperature for 1 hour.

Ice (50 g) was added and the slurry partitioned between water and DCM.The organic phase was washed with aqueous NaHCO₃ solution, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography eluting with DCM to give 7.05 g (76%)of 1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate (A9) as a brown oil.

LC/MS (m/z, MH⁺): 326

Intermediate (A10). Methyl1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

To a solution of1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate (A9) (7 g, 21.46 mmol) in DMF (20 ml) and MeOH(40 ml), were added Pd(dppf)C₂ (991.51 mg, 1.29 mmol) anddiisopropylethylamine (7.5 ml). The black suspension was carbonylated inan autoclave at 70° C. under 5 bars of CO for 18 hours.

The reaction mixture was filtered, then the filtrate was partiallyconcentrated under reduced pressure. AcOEt and water were added to theresidue obtained. The organic phase was washed with water and aqueousHCl 0.5 N, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography eluting withDCM to give 3.4 g (67%) of methyl1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate(A10) as a colorless oil.

LC/MS (m/z, MH⁺): 237

Intermediate (B5). Methyl4-fluoro-9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl1-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate(A10) (1.15 g, 4.87 mmol) in THF (25 ml) cooled at −10° C., was addeddropwise potassium bis(trimethylsilyl)amide (1.94 g, 9.74 mmol),followed by N,N-bis(trifluoromethylsulfonyl)aniline (1.95 g, 5.35 mmol).The reaction mixture was stirred for 30 minutes at −10° C. and 20 hoursat room temperature. The reaction mixture was cooled to 0° C. and water(500 ml) and AcOEt (200 ml) were added. The organic phase was dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography eluting with DCM to give 1.25 g (69%)of methyl4-fluoro-9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(B5) as an oil which was used as such in the following step.

LC/MS (m/z, MH⁺): 369

Intermediate (C7). Methyl4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution under argon of methyl4-fluoro-9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(B5) (1.53 g, 4.15 mmol),(S)-1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine(1) (1.60 g, 4.57 mmol), in dioxane (10 ml) and water (0.5 ml) wereadded Pd(dppf)Cl₂, complex with DCM (191.98 mg, 0.25 mmol) and Cs₂CO₃(2.85 g, 8.72 mmol). The reaction mixture was stirred at 80° C. for 1hour. After cooling to room temperature, the reaction mixture was pouredto a mixture of water (20 ml) and AcOEt (50 ml). The organic phase waswashed with brine, dried over MgSO₄, filtered on celite and concentratedunder reduced pressure. The residue was purified by flash chromatographyeluting with isopropylether/MeOH 95/05 to give 0.7 g (39%) of methyl4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(C7) as a yellow oil.

LC/MS (m/z, MH⁺): 442

Intermediate (D8). Methyl8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide

To a solution of methyl4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(C7) (900 mg, 2.04 mmol), in DCM (30 ml) was added pyridinium tribromide(880.11 mg, 2.75 mmol). The reaction mixture was stirred under argon for30 minutes at room temperature. Water (30 ml) was added then organicphase was dried over MgSO₄, and concentrated under reduced pressure. Theobtained meringue was purified by flash chromatography eluting with agradient of DCM/MeOH from 100/0 to 95/05 to give 0.8 g (63%) of methyl8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide (D8) as an orange meringue.

LC/MS (m/z, MH⁺): 520

EXAMPLES Example 1.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-3-ol

Method A:

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol(D2) (80 mg, 173.8 μmol) in dioxane/water (80/20; V/V; 4 ml), were added4-hydroxyphenyl-boronic acid (23.97 mg, 173.77 μmol), Cs₂CO₃ (119.02 mg,364.92 μmol), and Pd(dppf)Cl₂ (8.51 mg, 10.43 μmol). The reactionmixture was microwaved at 90° C. for 30 minutes, and purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 10%) togive a solid which was further purified on strong cation exchange (SCX)column to give 58 mg (71%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-3-ol.

Example 3.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol(D2) (80 mg, 173.8 μmol) in dioxane/water (80/20; V/V; 4 ml), were added5-indolylboronic acid (30.77 mg, 191.15 μmol), Cs₂CO₃ (119.02 mg, 364.92μmol), and Pd(dppf)C₂ (8.51 mg, 10.43 μmol). The reaction mixture wasmicrowaved at 90° C. for 30 minutes, and purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 10%) togive a solid which was further purified on strong cation exchange (SCX)column to give 12 mg (14%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol.

Example 4. 6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-3-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol(D2) (80 mg, 173.8 μmol) in dioxane/water (80/20; V/V; 4 ml), were added2-chloro-4-fluorophenylboronic acid (23.10 mg, 132.50 μmol), Cs₂CO₃(119.02 mg, 364.92 μmol), and Pd(dppf)C₂ (8.51 mg, 10.43 μmol). Thereaction mixture was microwaved at 90° C. for 30 minutes, and purifiedby column chromatography eluting with a gradient of MeOH in DCM (0% to10%) to give a solid which was further purified on strong cationexchange (SCX) column to give 50 mg (74%) of6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-3-ol.

Example 5. 6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (60 mg, 130.33 μmol) in dioxane/water (80/20; V/V; 3 ml), wereadded 2-chloro-4-fluorophenylboronic acid (23.43 mg, 130.33 μmol),Cs₂CO₃ (89.26 mg, 273.69 μmol), and Pd(dppf)Cl₂ (6.39 mg, 7.82 μmol).The reaction mixture was microwaved at 90° C. for 1 hour and purified bycolumn chromatography eluting with a gradient of methanol indichloromethane (0% to 10%) to give a solid which was further purifiedon strong cation exchange (SCX) column to give 52 mg (78.2%) of6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 9.6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (60 mg, 130.33 μmol) in dioxane/water (80/20; V/V; 3 ml), wereadded 2-fluoro-4-methylphenylboronic acid (22.99 mg, 143.36 μmol),Cs₂CO₃ (89.26 mg, 273.69 μmol), and Pd(dppf)Cl₂ (6.39 mg, 7.82 μmol).The reaction mixture was heated at 80° C. for 1 hour and purified bycolumn chromatography eluting with a gradient of MeOH in DCM (0% to 10%)to give a solid which was further purified on strong cation exchange(SCX) column to give 52 mg (82%) of6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 11.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (60 mg, 130.33 μmol), in dioxane/water (80/20; V/V; 3 ml), wereadded (4-hydroxyphenyl)boronic acid (17.98 mg, 130.33 μmol), Cs₂CO₃(89.26 mg, 273.69 μmol), and Pd(dppf)Cl₂ (6.39 mg, 7.82 μmol). Thereaction mixture was microwaved at 90° C. for 40 minutes and poured inwater. The aqueous phase was washed with DCM/MeOH solution (95/5; V/V)and the organic extracts dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by column chromatography eluting witha gradient of MeOH in DCM (0% to 10%) to give a solid which was furtherpurified on strong cation exchange (SCX) column to give 52 mg (41%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 21.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-indolin-5-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (50 mg, 108.61 μmol), in dioxane/water (80/20; V/V; 3 ml), wereadded 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (26.62 mg,108.61 μmol), Cs₂CO₃ (74.39 mg, 228.07 μmol), and Pd(dppf)Cl₂ (5.32 mg,6.52 μmol).

The reaction mixture was microwaved at 90° C. for 45 minutes andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 10%) togive 32 mg (59%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-indolin-5-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 25.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (139.3 mg, 302.58 μmol), in dioxane (2 ml) and water (1 ml), wasadded1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(81.01 mg, 363.09 μmol), Cs₂CO₃ (197.17 mg, 605.15 μmol), andPd(dppf)Cl₂ (13.28 mg, 18.15 μmol). The reaction mixture was heated at82° C. for 1.5 hours and partitioned between water and DCM. The aqueousphase was washed with DCM and the organic phase was concentrated underreduced pressure. The residue was purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 10%) to give a solid whichwas further purified on strong cation exchange (SCX) column to give 63.7mg (44.2%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 26.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of4-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (Example 24, 78.2 mg, 138.97 μmol), in MeOH (1.5ml) was added HCl (120 μl, 4N dioxane solution). The reaction mixturewas stirred at room temperature for 2.5 hours and concentrated underreduced pressure. The residue was purified by strong cation exchange(SCX) column to give 60.9 mg (94.7%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 29.6-(2-fluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (125.5 mg, 272.60 μmol), in dioxane (2 ml) and water (1 ml), wereadded 2-fluoro-4-methoxyphenylboronic acid (66.73 mg, 384.80 μmol),Cs₂CO₃ (177.64 mg, 545.20 μmol), and Pd(dppf)Cl₂ (11.97 mg, 16.36 μmol).The reaction mixture was heated at 90° C. for 1 hour and partitionedbetween water and DCM. The aqueous phase was washed with DCM and theorganic phase concentrated under reduced pressure. The residue waspurified by column chromatography eluting with a gradient of MeOH indiisopropyl ether (0% to 10%) to give a solid which was further purifiedon strong cation exchange (SCX) column to give 78 mg (56.6%) of6-(2-fluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 36.5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-olStep 1. Tert-butyl(3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(E1)

To a solution of9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(B2) (6.56 g, 16.72 mmol) in dioxane (45 ml), was added tert-butyl(3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate(c) (6.51 g, 16.72 mmol), Cs₂CO₃ (23 ml, 34.50 mmol), and Pd(dppf)C₂(1.44 g, 1.67 mmol). The reaction mixture was stirred at roomtemperature for 24 hours, and partitioned between water and AcOEt. Theaqueous phase was extracted with AcOEt and the organic phase dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by column chromatography, eluting with a mixture of heptane andDCM (60/40; V/V) to give 7.188 g (85%) of tert-butyl(3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(E1).

LC/MS (m/z, MH⁺): 507

Step 2. Tert-butyl(3S)-3-(4-{8-bromo-3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(F1)

To a solution of tert-butyl(3S)-3(4-{3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(E1) (7.18 g, 14.20 mmol) in THF (60 ml), was added pyridiniumtribromide (5.00 g, 15.62 mmol). The reaction mixture was stirred atroom temperature for 1 hour, and partitioned between water and AcOEt.The aqueous phase was extracted with AcOEt and the organic phase driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography, eluting with a mixture ofDCM and MeOH (96/4; V/V) to give 3.43 g (41.3%) of tert-butyl(3S)-3-(4-{8-bromo-3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(F1).

LC/MS (m/z, MH+): 484 and 486 (M-BOC).

Step 3. Tert-butyl(3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(G1)

To a solution of(3S)-3-(4-{8-bromo-3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(F1) (500 mg, 855.37 μmol) in dioxane (5 ml), was added2-fluoro-4-methylphenylboronic acid (150.89 mg, 940.91 μmol), Cs₂CO₃(2.5 ml, 3.75 mmol), and Pd(dppf)Cl₂ (65.88 mg, 85.54 μmol). Thereaction mixture was heated at 80° C. for 2 hours, and partitionedbetween water and AcOEt. The aqueous phase was extracted with AcOEt andthe organic phase dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography,eluting with a mixture of heptane and DCM (50/50; V/V) to give 285 mg(54.3%) of tert-butyl(3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(G1).

LC/MS (m/z, MH+): 614

Step 4.8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate hydrochloride salt (H1)

To a solution of tert-butyl(3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate(G1) (295 mg, 480.65 μmol) in MeOH (5 ml), was added hydrochloric acidin (4N, 1.20 ml, 4.80 mmol). The reaction mixture was stirred at roomtemperature for 2 hours and concentrated under reduced pressure to givea solid which was triturated with diisopropyl ether, filtered and driedto give 221 mg (59.5%) of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate, as an hydrochloride salt (H1).

LC/MS (m/z, MH⁺): 514

Step 5.8-(2-Fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (J1)

To a solution of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(H1) (163 mg, 317.34 μmol) in DMF (3 ml), was added 3-fluoropropanoicacid (30.76 mg, 317.34 μmol), 4-dimethylaminopyridine (121.15 mg, 952.02μmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride(76.84 mg, 380.81 μmol). The reaction mixture was stirred at roomtemperature for 2 hours, and partitioned between water and AcOEt. Theaqueous phase was extracted with AcOEt and the organic phase dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by column chromatography, eluting with a mixture of DCM andMeOH (97/3; V/V) to give 180 mg (96.5%) of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (J1).

LC/MS (m/z, MH+): 588

Step 6.5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol(Ic)

To a solution of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (J1) (180 mg, 306.28 μmol) in diethylether (5ml), was added lithium aluminum deuteride (39.36 mg, 918.84 μmol). Thereaction mixture was stirred at room temperature for 2 hours, dilutedwith DCM and a solution of sodium potassium bis-tartrate (1N) was added.The solid formed was filtered and the filtrate was dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography, eluting with a mixture of DCM andMeOH (97/3; V/V) to give 36 mg (23.9%) of5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol(Ic).

Example 39. 6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol Step 1:9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D′)

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (2.03 g, 4.41 mmol), in dioxane (25 ml) and water (10 ml), wasadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.34g, 5.29 mmol), Cs₂CO₃ (2.88 g, 8.82 mmol), and Pd(dppf)Cl₂ (203.77 mg,264.56 μmol). The reaction mixture was heated at 70° C. for 45 minutes,and partitioned between DCM and water. The phases were separated and theorganic phase concentrated under reduced pressure. The residue was firstpurified by column chromatography eluting with a gradient of MeOH in DCM(0% to 10%) to give a crude solid, which was further separated onchiralpak AD 20 μm, eluting with a mixture of heptane, ethanol andtriethylamine (90/9.9/0.1; V/V/V) to give 967 mg (43%) of5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-8,9-dihydro-7H-benzocyclohepten-2-ol(D′).

LC/MS (m/z, MH⁺): 509

Step 2:6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-8,9-dihydro-7H-benzocyclohepten-2-ol(D′) (100.3 mg, 197.66 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 3-chloro-2-fluoroiodobenzene (60.83 mg, 237.19 μmol), Cs₂CO₃(128.93 mg, 395.31 μmol) and Pd(dppf)Cl₂ (9.68 mg, 11.86 μmol). Thereaction mixture was heated at 70° C. for 6 hours, and partitionedbetween DCM and water. The aqueous phase was washed with DCM and organicphases were dried and concentrated under reduced pressure. The residuewas purified by column chromatography eluting with a gradient of MeOH inDCM (0% to 10%) to give a solid which was further purified on strongcation exchange (SCX) column to give 18 mg (18%) of6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 45.1-fluoro-6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D7) (60 mg, 125.43 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 2-fluoro-4-methylphenylboronic acid (22.12 mg, 137.97 μmol),Cs₂CO₃ (81.73 mg, 250.85 μmol), and Pd(dppf)Cl₂ (6.15 mg, 7.53 μmol).The reaction mixture was heated at 80° C. for 30 minutes and the solidformed, filtered and washed with dioxane. The filtrate was concentratedunder reduced pressure and the residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 10%) togive 45 mg (71%) of1-fluoro-6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 48.6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid Method C Step 1.8-(2-Fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate

To a solution of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(Example 9, 840 mg, 1.60 mmol), in DCM (30 ml), was added pyridine(387.4 μl, 4.79 mmol), and trifluoromethanesulfonic anhydride (839.5 μl,4.79 mmol). The reaction mixture was stirred at room temperature for 16hours, poured onto ice and partitioned between water and DCM. Theaqueous phase was washed with DCM and the gathered organic phases,washed successively with a saturated solution of NaHCO₃, and brine. Theorganic phase was dried over MgSO₄, filtered, and the filtrate wasconcentrated under reduced pressure to give 860 mg (86.6%) of crude8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate.

LC/MS (m/z, MH⁺): 622

Step 2. Methyl8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

To a solution of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate (860 mg, 1.35 mmol), in DMF (10 ml) and MeOH(5 ml), was added triethylamine (1 ml), Pd(OAc)₂ (60.52 mg, 269.54μmol), and 1,3-bis(diphenylphosphino)propane (dppp) (115.80 mg, 269.54μmol). The reaction mixture was heated at 40° C., under an atmosphere ofCO (2 bars), for 16 hours, and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with a mixture ofcyclohexane and AcOEt (80/20; V/V) to give 400 mg (55.8%) of methyl8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

LC/MS (m/z, MH⁺): 532

Step 3.8-(2-Fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylicacid

To a solution of methyl8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate(390 mg, 733.59 μmol), MeOH (20 ml), was added NaOH solution (5N, 1.5ml). The reaction mixture was heated at 60° C., for 2 hours, andconcentrated under reduced pressure. The residue was taken up into water(25 ml), and acidified with aqueous HCl (5N, 1.5 ml), and the solidformed was filtered, washed with water and dried under vacuum. Theresidue was purified by trituration in diisopropyl ether to give 180 mg(47.4%) of8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylicacid.

Example 51.6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid Method B Step 1:6-(2,4-Dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-Carboxylicacid methyl ester

To a solution of methyl8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide (D5) (150 mg, 298.56 μmol), in dioxane (12 ml) and water (2ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μmol),Cs₂CO₃ (204.48 mg, 626.97 μmol), and Pd(dppf)Cl₂ (14.63 mg, 17.91 μmol).The reaction mixture was heated at 90° C. for 3 hours, and partitionedbetween AcOEt and water. The phases were separated and the organic phasewashed with brine, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by column chromatography eluting witha mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg(47%) of6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylicacid methyl ester.

LC/MS (m/z, MH⁺): 568

Step 2:6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid

To a solution of6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylicacid methyl ester (80 mg, 140.72 μmol) in MeOH (5 ml) was added asolution of NaOH (562.88 μl, 5 M) and the reaction mixture was heated at60° C. for 5 hours and the solvent removed under reduced pressure. Theresidue was taken up in water (10 ml) and aqueous HCl (5 M) added to pH7. The slurry was extracted with DCM, dried over MgSO₄ and concentratedunder reduced pressure. The solid was purified by column chromatographyeluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) togive 60 mg (77%) of6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid.

Example 63.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid hydrochloride Step 1:6-(4-Methoxy-2-methyl-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylicacid methyl ester

To a solution of methyl8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide (D5) (250 mg, 497.60 μmol), in dioxane (12 ml) and water (2ml), was added 4-methoxy-2-methylphenyl-boronic acid (90.85 mg, 547.36μmol), Cs₂CO₃ (340.81 mg, 1.04 mmol), and Pd(dppf)Cl₂ (24.38 mg, 29.86μmol). The reaction mixture was heated at 90° C. for 2 hours, andpartitioned between AcOEt and water. The phases were separated and theorganic phase washed with brine, dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) togive 280 mg (100%) of crude6-(4-methoxy-2-methyl-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylicacid methyl ester.

LC/MS (m/z, MH⁺): 544

Step 2: 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid hydrochloride

To a solution of6-(4-methoxy-2-methyl-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylicacid methyl ester (280 mg, 543.668 μmol) in MeOH (10 ml) was added asolution of NaOH (5 M, 1.5 ml) and the reaction mixture was heated at60° C. for 6 hours and the solvent removed under reduced pressure. Theresidue was taken up in water (25 ml) and aqueous HCl (5 M) was added topH 7. The slurry was extracted with DCM, dried over MgSO₄ andconcentrated under reduced pressure. The solid was purified by columnchromatography eluting with a mixture of DCM, acetonitrile and MeOH(90/5/5; V/V/V) to give a solid. This solid was triturated indiisopropyl ether with anhydrous HCl (2 M in diethyl ether) to give asolid which was filtered and dried to give 134 mg (46%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid hydrochloride.

Example 70. 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol Step 1:1-[5-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-2,2-dimethyl-2,3-dihydro-indol-1-yl]-ethanone

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (93.8 mg, 203.75 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone(64.72 mg, 205.32 μmol), Cs₂CO₃ (132.90 mg, 407.49 μmol), andPd(dppf)Cl₂ (9.98 mg, 12.22 μmol). The reaction mixture was heated at72° C. for 45 minutes, and partitioned between DCM and water. The phaseswere separated on hydrophobic interaction column and the organic phaseconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 10%) togive a solid which was further purified on strong cation exchange (SCX)column to give 77 mg (67%) of1-[5-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-2,2-dimethyl-2,3-dihydro-indol-1-yl]-ethanone.

LC/MS (m/z, MH⁺): 569

Step 2:6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of(S)-1-(5-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl)-2,2-dimethylindolin-1-yl)ethanone(73 mg, 128.36 μmol) in dioxane (1.9 ml), was added aqueous HCl (1N, 1.5ml) and the reaction mixture heated in a microwave oven at 120° C. for 2hours. The reaction mixture was poured onto a saturated aqueous solutionof NaHCO₃, and extracted with DCM. The phases were separated onhydrophobic interaction column and the organic phase concentrated underreduced pressure. The residue was purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 10%) to give 39 mg (58%)of6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 73.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,4-tetrahydroquinolin-6-yl)-8,9-dihydro-7H-benzo[7]annulen-2-olStep 1:6-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (93.4 mg, 202.88 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(85.18 mg, 237.09 μmol), Cs₂CO₃ (132.33 mg, 405.75 μmol), andPd(dppf)Cl₂ (9 9.94 mg, 12.17 μmol). The reaction mixture was heated at72° C. for 45 minutes, and partitioned between DCM and water. The phaseswere separated on hydrophobic interaction column and the organic phaseconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 10%) togive 75 mg (60.3%) of6-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

LC/MS (m/z, MH⁺): 613

Step 2:6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of6-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester in DCM (2.4 ml) was added HCl (1M in diethylether,1.17 ml) and the reaction mixture stirred at room temperature for 18hours. A saturated aqueous NaHCO₃ solution was added, and the aqueousphase was extracted with DCM. The phases were separated on hydrophobicinteraction column and the organic phase concentrated under reducedpressure. The residue was purified by column chromatography eluting witha gradient of MeOH in DCM (0% to 10%) to give 57.3 mg (95.1%) of6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 75.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (92.9 mg, 201.79 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 4-(trifluoromethoxy)phenylboronic acid (54.12 mg, 254.93 μmol),Cs₂CO₃ (131.63 mg, 403.58 μmol), and Pd(dppf)Cl₂ (9.89 mg, 12.11 μmol).The reaction mixture was heated at 72° C. for 45 minutes, andpartitioned between DCM and water. The phases were separated onhydrophobic interaction column and the organic phase concentrated underreduced pressure. The residue was purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 10%) to give 71.3 mg(61.4%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 76.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (74.9 mg, 162.69 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 4-methoxyphenylboronic acid (34.49 mg, 222.45 μmol), Cs₂CO₃(131.91 mg, 404.45 μmol), and Pd(dppf)Cl₂ (9.91 mg, 12.13 μmol). Thereaction mixture was heated at 72° C. for 45 minutes, and partitionedbetween DCM and water. The phases were separated on hydrophobicinteraction column and the organic phase concentrated under reducedpressure. The residue was purified by column chromatography eluting witha gradient of MeOH in DCM (0% to 10%) to give a solid which was furtherpurified on strong cation exchange (SCX) column to give 63.9 mg (64.8%)of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 82.6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D7) (60 mg, 125.43 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 6-ethoxy-2-fluoropyridin-3-yl boronic acid (25.52 mg, 137.97μmol), Cs₂CO₃ (171.05 mg, 525.0 μmol), and Pd(dppf)Cl₂ (9.66 mg, 12.54μmol). The reaction mixture was heated at 60° C. for 1 hour andpartitioned between water and AcOEt. The aqueous phase was washed withAcOEt and the organic extracts dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified twice bycolumn chromatography eluting first with a mixture of diisopropylether/MeOH (90/10; V/V) and with a mixture of DCM/MeOH (98/2) to give 38mg (56.3%) of6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 107.6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (74.9 mg, 162.69 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 2-ethoxypyrimidin-5-yl boronic acid (30.06 mg, 178.96 μmol),Cs₂CO₃ (106.12 mg, 325.38 μmol), and Pd(dppf)C₂ (7.97 mg, 9.76 μmol).The reaction mixture was heated at 72° C. for 1 hour, partitionedbetween water and DCM and phases separated on hydrophobic partitioncolumn. The organic solvents were concentrated under reduced pressureand the residue was purified by column chromatography eluting with agradient of MeOH in DCM (0% to 10%) to give a solid which was furtherpurified on strong cation exchange (SCX) column to give 47.3 mg (57.7%)of6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 108.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (90 mg, 195.49 μmol), in dioxane/water (80/20; V/V; 4 ml), wasadded 2-methoxy-5-pyridineboronic acid (37.77 mg, 234.59 μmol), Cs₂CO₃(133.89 mg, 410.53 μmol), and Pd(dppf)Cl₂ (9.58 mg, 11.73 μmol). Thereaction mixture was heated in a microwave at 90° C. for 30 minutes, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 4%) to givea solid which was further purified on strong cation exchange (SCX)column to give 59 mg (61.8%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 109.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methoxy-4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (90 mg, 195.49 μmol), in dioxane/water (80/20; V/V; 4 ml), wasadded 2-methoxypyridine-4-boronic acid (36.99 mg, 234.59 μmol), Cs₂CO₃(133.89 mg, 410.53 μmol), and Pd(dppf)Cl₂ (9.58 mg, 11.73 μmol). Thereaction mixture was heated in a microwave at 90° C. for 30 minutes, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with a gradient of MeOH in DCM (0% to 4%) to givea solid which was further purified on strong cation exchange (SCX)column to give 60 mg (62.8%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methoxy-4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 114. 1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D7) (60 mg, 125.43 μmol), in dioxane (1 ml) and water (0.5 ml), wasadded 4-(trifluoromethoxy)phenylboronic acid (29 mg, 137.97 μmol),Cs₂CO₃ (81.73 mg, 250.85 μmol), and Pd(dppf)Cl₂ (6.15 mg, 7.53 μmol).The reaction mixture was heated at 80° C. for 30 minutes and the solidfiltered and washed with dioxane. The filtrate was concentrated undereduced pressure and the residue was purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 10%) to give 45 mg (71%)of 1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 163.[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate Step 1: Diethyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-benzo[7]annulen-3-yl phosphate

To a solution of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol(Example 75, 312 mg, 576.10 μmol), in acetonitrile (3 ml), was addedtriethylamine (353.1 μl, 2.54 mmol), and diethyl chlorophosphate (249.76μl, 1.73 mmol). The reaction mixture was stirred at room temperature for28 hours, and concentrated under reduced pressure. The residue waspurified by strong cation exchange (SCX) column to give 256 mg (65.6%)of diethyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-benzo[7]annulen-3-ylphosphate.

LC/MS (m/z, MH⁺): 678

Step 2: [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate

To a solution of diethyl9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-benzo[7]annulen-3-ylphosphate (256 mg, 377.77 μmol), in acetonitrile (6 ml), was addediodotrimethylsilane (277.12 μl, 1.89 mmol). The reaction mixture wasstirred at room temperature for 1 hour, and concentrated under reducedpressure. The residue was purified by strong cation exchange (SCX)column and reverse phase column chromatography, eluting with a gradientof acetonitrile in water (20% to 80%) to give 167 mg (70.3%) of[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogenphosphate.

Example 174. 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid hydrochloride Step 1: Methyl8-(2,2-dimethyl-2,3-dihydro-1H-indol-5-yl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylatehydrobromide (D5) (500 mg, 845.91 μmol), in dioxane (12 ml) and water (2ml), was added1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone(279.98 mg, 888.21 μmol), Cs₂CO₃ (744.91 mg, 2.28 mmol), and Pd(dppf)Cl₂(41.45 mg, 50.75 μmol). The reaction mixture was heated in a microwaveat 110° C. for 1 hour, DCM was added and the organic phase washed withsaturated NH₄Cl solution. The organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with a mixture of DCM,acetonitrile and MeOH (96/2/2; V/V/V) to give 250 mg (48.4%) of methyl8-(2,2-dimethyl-2,3-dihydro-1H-indol-5-yl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

LC/MS (m/z, MH⁺): 611

Step 2:6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid hydrochloride

To a solution of methyl8-(2,2-dimethyl-2,3-dihydro-1H-indol-5-yl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (240 mg, 392.95 μmol) inMeOH (20 ml) was added NaOH (15.72 mg, 392.95 μmol) and the reactionmixture was heated under reflux for 3 hours and the solvent removedunder reduced pressure. The residue was taken up in water (15 ml), HCl(5 M, 1 ml) was added and the reaction mixture was heated under refluxfor 2 hours. NaOH solution was added to pH 7, and the aqueous phaseextracted with DCM. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue wastriturated with diisopropyl ether, filtered and dried to give 211 mg(90.8%) of6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid hydrochloride.

Example 189.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyridin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-olStep 1:9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate(D3) (1 g, 1.84 mmol), in dioxane (10 ml) and water (5 ml), was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (559.65 mg,2.20 mmol), Cs₂CO₃ (1.20 g, 3.67 mmol), and Pd(dppf)Cl₂ (84.87 mg,110.19 μmol). The reaction mixture was heated under reflux for 24 hours,and partitioned between DCM and water. The aqueous phase was washed withDCM and the gathered organic phase dried over hydrophobic partitioncolumn, and evaporated under reduced pressure. The residue was purifiedby column chromatography eluting with a mixture of DCM and MeOH (98/2;V/V) to give 426 mg (39.2%) of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate.

LC/MS (m/z, MH+): 592 (M+H).

Step 2:[9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl]boronicacid

To a solution of9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl2,2-dimethylpropanoate (426 mg, 720.13 μmol), in MeOH (10 ml), was addedNaOH (2N, 2.16 ml, 4.32 mmol). The reaction mixture was stirred at roomtemperature for 1.5 hour, and HCl (2N, 2.2 ml) was added. The aqueousphases was washed with DCM, and evaporated under reduced pressure. Theresidue was triturated with a mixture of DCM and MeOH (95/5, V/V),filtered and concentrated under reduced pressure to give 100 mg (32.7%)of crude[9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl]boronicacid.

LC/MS (m/z, MH+): 426 (M+H).

Step 3:5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyridin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of[9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl]boronicacid (100 mg, 235.12 μmol), in dioxane (8 ml) and water (2 ml),4-bromopyridine 1-oxide (57.28 mg, 329.17 μmol), Cs₂CO₃ (161.04 mg,493.76 μmol) and Pd(dppf)Cl₂ (11.52 mg, 14.11 μmol). The reactionmixture was heated at 90° C. for 2 hours, and concentrated under reducedpressure. The residue was purified by column chromatography eluting witha gradient of MeOH in DCM (0% to 4%) to give a solid which was furtherpurified on strong cation exchange (SCX) column to give 21 mg (18.8%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyridin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 203.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-tetrahydropyran-4-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of6-(3,6-dihydro-2H-pyran-4-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(Example 202, 110 mg, 237.28 μmol) in AcOEt (3 ml) and ethanol (5 ml),was added palladium on carbon (10%, 2.53 mg, 23.73 μmol). The reactionmixture was stirred at 50° C. under hydrogen atmosphere (5 bars) for 2hours. The reaction mixture was filtered on celite, washed with MeOH,and the filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography eluting with a mixture of DCM andMeOH (90/10; V/V)) to give 61 mg (55%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-tetrahydropyran-4-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 204.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-olStep 1:6-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (500 mg, 1.09 mmol), in dioxane/water (80/20; V/V, 25 ml), wasadded 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacoyl ester (412.93mg, 1.52 mmol), Cs₂CO₃ (743.85 mg, 2.28 mmol), and Pd(dppf)C₂ (53.22 mg,65.16 μmol). The reaction mixture was heated at 80° C. for 30 minutes,and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with a gradient of MeOH in DCM (0% to 4%)to give a solid which was further purified on strong cation exchange(SCX) column to give 485 mg (85.9%) of6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol.

LC/MS (m/z, MH⁺): 520

Step 2:6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

To a solution of6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(485 mg, 933.31 μmol), in AcOEt (10 ml) and ethanol (10 ml), was addedpalladium on carbon (10%, 9.93 mg, 93.33 μmol). The reaction mixture wasstirred at 50° C. under hydrogen atmosphere (5 bars) for 24 hours. Thereaction mixture was filtered over celite, rinsed with MeOH and thefiltrate was concentrated under reduced pressure to give 487 mg (100%)of crude6-(1,4-dioxa-spiro[4.5]dec-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol.

LC/MS (m/z, MH⁺): 522

Step 3:4-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-cyclohexanone

To a solution of crude6-(1,4-dioxa-spiro[4.5]dec-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(487 mg, 933.53 μmol) in acetone (2 ml) was added concentrated aqueousHCl (1.4 ml) and the reaction mixture was stirred at room temperaturefor 4 days. A saturated aqueous solution of NaHCO₃ and DCM was added andthe phases were separated on hydrophobic interaction column. The organicphase was concentrated under reduced pressure and the residue purifiedby column chromatography eluting with a mixture of MeOH in DCM (3/97;V/V) to give 390 mg (87.5%) of4-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-cyclohexanone.

LC/MS (m/z, MH⁺): 478.

Step 4:5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of4-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-cyclohexanone(200 mg, 418.74 μmol), in MeOH (4 ml), was added sodium borohydride(147.3 mg, 3.89 mmol). The reaction mixture was stirred at roomtemperature for 4 days, and water was added. A solid forms which wasfiltered, rinsed with water and purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 10%) to give 28 mg (14%)of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

Example 207.6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (200 mg, 434.42 μmol) in dioxane/water (80/20; V/V, 10 ml), wasadded2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(127.24 mg, 521.30 μmol), Cs₂CO₃ (297.53 mg, 912.28 μmol), andPd(dppf)Cl₂ (20.08 mg, 26.07 μmol). The reaction mixture was heated at90° C. for 30 minutes, and the solvent was concentrated under reducedpressure. The residue was purified by column chromatography eluting witha gradient of MeOH in DCM (0% to 10%) to give a solid which was furtherpurified on strong cation exchange (SCX) column to give 95 mg (44%) of6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 208.6-(4,4-difluorocyclohexyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol(95 mg, 190.92 μmol), in AcOEt (3 ml) and ethanol (5 ml) was addedpalladium on carbon (10%, 2.03 mg, 19.09 μmol). The reaction mixture wasstirred at 50° C. under hydrogen atmosphere (5 bars) for 2 hours andfiltered on celite, rinsed with MeOH and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with a mixture of MeOH in DCM (3/97; V/V) to give70 mg (73.4%) of6-(4,4-difluorocyclohexyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 213.6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid Step 1: Methyl8-(2-chloro-4-fluorophenyl)-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate,hydrobromide (D8) (200 mg, 332.60 μmol) in dioxane (15 ml) was added2-chloro-4-fluorophenyl boronic acid (69.59 mg, 399.12 μmol), Cs₂CO₃(465.64 μl, 698.46 μmol), and Pd(dppf)Cl₂ (15.37 mg, 19.96 μmol). Thereaction mixture was heated at 70° C. for 1 hour, and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 5%), to give a solid whichwas further purified on strong cation exchange (SCX) column to give 170mg (89.7%) of methyl8-(2-chloro-4-fluorophenyl)-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

LC/MS (m/z, MH⁺): 570

Step 2:6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid

To a solution of methyl8-(2-chloro-4-fluorophenyl)-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate(170 mg, 298.22 μmol) in MeOH (150 ml), was added NaOH 5 M (238.58 μl,1.19 mmol). The reaction mixture was heated at 90° C. for 2 hours,aqueous HCl (5 N) was added, and purified on strong cation exchange(SCX) column to give 65 mg (39.2%) of6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid.

Example 215.5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

To a solution of8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(D4) (306.6 mg, 665.97 μmol), in dioxane (4 mL) and water (0.5 ml), wasadded 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (201mg, 823.43 μmol), Cs₂CO₃ (557 mg, 1.71 mmol), and Pd(dppf)Cl₂ (70 mg,85.72 μmol). The reaction mixture was heated at 72° C. for 4 hours andpartitioned between water and DCM. The phases were separated onhydrophobic interaction column and the organic phase concentrated underreduced pressure. The residue was purified by column chromatographyeluting with a gradient of MeOH in DCM (0% to 10%) to give 26 mg (8%) of5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Some compounds of formula (I) were subjected to pharmacological testsfor determining their antagonist and degradation effects on estrogenreceptors.

Test A: Biochemical Antagonist Activity on Wild Type (WT) and MutantsEstrogen Receptors

Test A involves measuring the in vitro antagonist activity of a compoundof formula (I) on estrogen receptors.

The measurements of the antagonist activities were made using anestrogen receptor coactivator assay as described hereunder.

Antagonistic potency of compounds was evaluated using LanthaScreen®TR-FRET ERα Coactivator Assay (ThermoFisher) with modifications. It is acompetition assay, where binding of a test compound to a complexcomprised of (i) His6-ERα298-554 protein representing ERα ligand-bindingdomain, (ii) Tb-labeled His6 antibody, (iii) a fluorescein-labeled PGC1acoactivator peptide (EAEEPSLLKKLLLAPANTQ), and (iv) estradiol, resultsin a decrease of the TR-FRET signal due to dissociation of thecoactivator peptide. His6-ERα298-554 proteins were expressed as WT orD538G or Y537S mutants in E. coli and purified by affinitychromatography. The assay works in a homogeneous mix-and-read format. Ina typical experiment, a 4 μL mixture of 0.5 nM His6-ERα298-554, 0.5 nMTb-labeled His6 antibody, 250 nM PGC1a peptide, and 3 nM estradiol in100 mM potassium phosphate, pH 7.4, 0.01% Tween-20, 0.02% NaN₃, 5 mMDTT, was added to 40 nL test compound in DMSO and incubated overnight atroom temperature. The TR-FRET 520:495 nm emission ratio was calculatedand used to determine the IC50 value from a dose response curve fit tothe 4-parameter logistic equation.

The antagonist activity with respect to estrogen receptors in this testis given by the concentration which inhibits 50% of the estrogenreceptor activity (or IC50) in nM.

The Table 2 below indicates the biochemical results of antagonistactivity on WT and mutants estrogen receptors for compounds of formula(I), and demonstrates that the compounds tested have an antagonistactivity regarding estrogen receptors.

TABLE 2 Antagonism Antagonism Antagonism WT D538G Y537S Examples IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) Example 1 7 32 22 Example 2 5 30 22 Example 337 268 139 Example 4 19 117 68 Example 5 7 21 21 Example 6 2 4 3 Example7 5 36 19 Example 8 3 15 8 Example 9 3 20 10 Example 10 2 5 3 Example 112 4 3 Example 12 3 18 10 Example 13 4 19 11 Example 14 3 15 7 Example 155 37 24 Example 16 14 109 63 Example 17 3 24 15 Example 18 5 28 21Example 19 8 49 26 Example 20 2 12 9 Example 21 7 30 26 Example 22 7 4526 Example 23 3 9 4 Example 24 152 759 475 Example 25 284 937 726Example 26 199 443 341 Example 27 3 10 6 Example 28 2 5 4 Example 29 2 42 Example 30 5 20 9 Example 31 2 19 12 Example 32 3 32 24 Example 33 341 24 Example 34 2 18 11 Example 35 12 244 134 Example 36 3 90 50Example 37 14 309 241 Example 38 39 652 651 Example 39 4 76 53 Example40 16 289 224 Example 41 10 177 133 Example 42 2 55 33 Example 43 0.8 1411 Example 44 1 16 12 Example 45 2 40 23 Example 46 1 21 16 Example 47 231 23 Example 48 44 1119 549 Example 49 1 11 6 Example 50 10 208 113Example 51 15 389 221 Example 52 2 49 29 Example 53 244 3541 2857Example 54 1 8 5 Example 55 23 635 338 Example 56 15 389 204 Example 573 56 39 Example 58 2 37 24 Example 59 2 57 34 Example 60 3 68 39 Example61 10 178 99 Example 62 20 337 178 Example 63 6 132 72 Example 64 6 14988 Example 65 2 38 25 Example 66 12 217 127 Example 67 5 145 85 Example68 12 184 109 Example 69 5 172 90 Example 70 2 36 22 Example 71 1 28 18Example 72 31 895 498 Example 73 4 59 40 Example 74 2 28 26 Example 7556 1295 679 Example 76 2 40 23 Example 77 1 19 13 Example 78 17 298 185Example 79 9 182 113 Example 80 13 389 203 Example 81 7 128 93 Example82 1 24 16 Example 83 51 842 648 Example 84 74 1464 964 Example 85 581111 735 Example 86 12 313 172 Example 87 9 150 93 Example 88 5 139 78Example 89 1 12 8 Example 90 13 263 190 Example 91 2 35 18 Example 92 34840 504 Example 93 2 29 24 Example 94 25 485 322 Example 95 12 243 150Example 96 20 307 196 Example 97 9 127 78 Example 98 1 18 12 Example 9918 804 280 Example 100 83 1329 1014 Example 101 14 269 163 Example 102 5123 71 Example 103 4 86 55 Example 104 2 30 17 Example 105 8 129 81Example 106 15 524 607 Example 107 42 977 507 Example 108 1 33 19Example 109 1 29 17 Example 110 14 274 168 Example 111 4 120 67 Example112 4 76 46 Example 113 34 633 434 Example 114 21 346 242 Example 115 686 71 Example 116 2 37 25 Example 117 12 238 163 Example 118 17 245 164Example 119 62 953 714 Example 120 38 585 357 Example 121 4 76 56Example 122 2 40 24 Example 123 4 72 46 Example 124 13 215 170 Example125 8 154 106 Example 126 33 661 541 Example 127 30 603 347 Example 12889 2046 1692 Example 129 23 474 290 Example 130 3 59 44 Example 131 15387 253 Example 132 77 1371 1249 Example 133 20 384 190 Example 134 2 2828 Example 135 59 1077 1226 Example 136 11 201 134 Example 137 28 595363 Example 138 50 697 323 Example 139 2 43 28 Example 140 52 996 685Example 141 27 475 436 Example 142 5 117 64 Example 143 4 100 57 Example144 46 759 645 Example 145 2 44 28 Example 146 9 152 67 Example 147 54982 583 Example 148 62 1037 916 Example 149 5 114 72 Example 150 91 17682148 Example 151 122 1641 >4000 Example 152 8 268 132 Example 153 4 7447 Example 154 10 191 117 Example 155 11 231 141 Example 156 90 885 1006Example 157 3 84 53 Example 158 5 106 63 Example 159 241 3816 2563Example 160 15 266 110 Example 161 23 396 169 Example 162 16 290 159Example 163 N/A* N/A* N/A* Example 164 8 191 121 Example 165 2 47 27Example 166 13 560 299 Example 167 3 42 33 Example 168 228 3844 >4000Example 169 46 868 787 Example 170 6 143 89 Example 171 2 33 20 Example172 95 1632 1072 Example 173 154 2346 1495 Example 174 31 707 429Example 175 1 20 14 Example 176 33 873 435 Example 177 289 >4000 2911Example 178 2 52 29 Example 179 46 755 538 Example 180 7 133 78 Example181 14 260 187 Example 182 10 176 120 Example 183 9 180 125 Example 18449 991 459 Example 185 67 1545 981 Example 186 6 118 75 Example 187 28476 321 Example 188 1 23 16 Example 189 183 2973 2414 Example 190 37 623444 Example 191 0 6 4 Example 192 1 18 11 Example 193 57 939 516 Example194 4 66 38 Example 195 2 56 34 Example 196 15 354 198 Example 197 11169 124 Example 198 62 1039 586 Example 199 1 21 15 Example 200 195 34503097 Example 201 6 125 74 Example 202 5 94 67 Example 203 3 69 48Example 204 2 50 29 Example 205 12 331 187 Example 206 27 606 374Example 207 3 58 39 Example 208 1 32 19 Example 209 33 703 543 Example210 11 283 162 Example 211 30 618 443 Example 212 84 2366 1111 Example213 22 529 334 Example 214 2 39 23 Example 215 4 88 57 Example 216 31743 431 Example 217 39 960 632 Example 218 61 1472 779 Example 219 841595 1094 N/A*: Not available. Prodrug of example 75

Test B: Cell Proliferation/Viability Assay on MCF7 (Breast Tumor Cells)WT and Mutants Cell Lines

Test B involves measuring the in vitro proliferation activity of acompound of formula (I) by analyzing the viability of the tumor cells.

The measurements of the viability were made using a breast cancer cellviability assay as described hereunder.

MCF7 cells expressing (and dependent) on mutants estrogen receptor Tyr537 Ser or Asp 538 Gly were generated by transfection of MCF7 parentalcells (ATCC) with expression vectors coding for different mutants ofestrogen receptor Tyr 537 Ser or Asp 538 Gly. The cells were firstselected by antibiotic (related to vector expression) and then selectedfor their growth dependence on estrogen receptor based on their abilityto grow in vitro in absence of estradiol (parental cell line die inabsence of estradiol).

MCF7 cells (ATCC) or MCF7 cells expressing (and dependent) on mutantsestrogen receptor Tyr 537 Ser or Asp 538 Gly were seeded in 384 wellsmicroplate at concentration of 1000 cells/30 μL per well in red phenolfree MEM medium containing 5% charcoal dextran striped FBS. Thefollowing day, 9 points serial 1:5 dilution of each compound were addedto the cells in 20 μL at final concentrations ranging from 3-0.000001μM. After 7 days of compound exposure, 50 μL of CellTiter-Glo (Promega)was added to the cells and relative luminescence arbitrary units (RLUs)were determined in luminescence plate reader (Envision device).CellTiter-Glo was added to 50 μL medium without cells to determine thebackground signal.

The percent of viability of each sample was determined as follows: (RLUsample−RLU background/RLU untreated−RLU background)*100=% viability.

The viability activity with respect to estrogen receptors in this testis given by the concentration which inhibits 50% of the viabilityactivity (or IC50) in nM.

The Table 3 below indicates the cell proliferation/viability assayresults on MCF7 (breast tumor cells) WT and mutants cell lines, forcompounds of formula (I), and demonstrates that the compounds testedhave a significant antiproliferative activity regarding estrogenreceptors.

TABLE 3 proliferation proliferation proliferation MCF7 MCF7 MCF7 (WT)D538G Y537S Examples IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) Example 1 0.6 0.1 3Example 2 1 0.1 6 Example 3 9 0.2 17 Example 4 5 0.2 11 Example 5 0.30.2 2 Example 6 3 0.1 3 Example 7 0.2 0.3 1 Example 8 4 0.1 6 Example 90.4 1 5 Example 10 7 0.4 15 Example 11 3 0.2 7 Example 12 28 2 35Example 13 0.5 0.4 5 Example 14 2 0.1 2 Example 15 0.2 0.4 4 Example 163 0.4 7 Example 17 0.2 0.3 2 Example 18 0.7 1 5 Example 19 5 0.4 19Example 20 5 0.1 14 Example 21 23 2 36 Example 22 6 30 306 Example 230.2 1 4 Example 24 63 7 71 Example 25 48 5 67 Example 26 25 4 31 Example27 0.2 1 8 Example 28 0.2 1 7 Example 29 0.5 1 3 Example 30 36 2 39Example 31 4 0.3 6 Example 32 0.3 1 3 Example 33 0.3 1 3 Example 34 0.20.4 2 Example 35 0.2 1 5 Example 36 0.3 0.4 4 Example 37 0.5 1 7 Example38 0.6 1 9 Example 39 0.2 1 4 Example 40 0.2 0.4 4 Example 41 0.2 1 4Example 42 0.4 1 6 Example 43 0.4 1 5 Example 44 0.2 1 3 Example 45 0.72 14 Example 46 0.6 1 8 Example 47 0.3 0.3 3 Example 48 0.7 2 13 Example49 0.4 1 5 Example 50 0.2 0.3 4 Example 51 0.4 1 10 Example 52 0.3 1 5Example 53 10 21 112 Example 54 0.1 0.2 2 Example 55 2 4 39 Example 560.5 2 10 Example 57 0.2 0.3 3 Example 58 0.3 1 4 Example 59 0.1 0.5 3Example 60 0.4 0.3 5 Example 61 0.3 1 4 Example 62 0.4 1 7 Example 630.4 1 5 Example 64 0.3 0.4 4 Example 65 0.1 1 2 Example 66 0.4 1 6Example 67 0.2 0.4 3 Example 68 0.2 0.3 2 Example 69 0.3 1 5 Example 700.2 1 8 Example 71 0.2 0.4 4 Example 72 0.6 1 14 Example 73 0.9 2 15Example 74 0.1 0.3 2 Example 75 0.5 1 7 Example 76 0.2 0.3 3 Example 770.1 0.3 2 Example 78 0.4 0.4 6 Example 79 6 0.6 12 Example 80 0.5 1 11Example 81 0.2 0.2 4 Example 82 0.8 1 8 Example 83 1 1 14 Example 84 0.71 13 Example 85 0.8 1 9 Example 86 0.4 1 5 Example 87 0.1 0.4 2 Example88 0.2 0.3 4 Example 89 0.2 0.3 3 Example 90 0.4 0.3 6 Example 91 0.10.2 1 Example 92 0.5 1 8 Example 93 0.2 1 4 Example 94 0.7 1 7 Example95 0.5 1 10 Example 96 0.8 1 5 Example 97 0.2 0.1 1 Example 98 0.4 0.3 2Example 99 0.4 1 3 Example 100 1 2 15 Example 101 0.8 1 6 Example 1020.1 0.3 1 Example 103 0.5 1 5 Example 104 0.1 0.1 1 Example 105 0.3 0.34 Example 106 1 3 54 Example 107 0.5 1 12 Example 108 0.2 0.1 1 Example109 0.2 0.1 2 Example 110 0.4 1 9 Example 111 0.2 0.2 3 Example 112 0.20.2 4 Example 113 0.6 2 11 Example 114 0.4 1 5 Example 115 0.3 1 5Example 116 0.1 1 2 Example 117 0.5 1 6 Example 118 0.2 0.2 2 Example119 0.7 2 8 Example 120 0.3 1 6 Example 121 0.3 1 2 Example 122 0.2 1 2Example 123 0.2 1 5 Example 124 0.3 1 4 Example 125 0.2 1 3 Example 1261 3 30 Example 127 0.1 0.4 1 Example 128 8 17 96 Example 129 0.1 0.3 5Example 130 0.2 1 5 Example 131 0.4 1 11 Example 132 0.7 2 19 Example133 1 2 29 Example 134 0.1 0.3 3 Example 135 1 3 21 Example 136 0.2 1 5Example 137 0.2 1 7 Example 138 0.8 3 19 Example 139 0.1 1 3 Example 1401 3 24 Example 141 0.3 1 5 Example 142 0.2 0.2 2 Example 143 0.7 1 5Example 144 2 2 25 Example 145 0.3 0.4 3 Example 146 0.4 1 4 Example 1472 2 20 Example 148 2 2 11 Example 149 0.7 1 6 Example 150 3 2 18 Example151 0.9 1 16 Example 152 0.4 0.3 4 Example 153 0.1 0.1 1 Example 154 0.40.3 4 Example 155 0.1 0.2 2 Example 156 2 4 11 Example 157 0.6 0.2 2Example 158 0.5 1 5 Example 159 8 11 112 Example 160 0.7 1 6 Example 1610.8 1 7 Example 162 0.6 1 3 Example 163 N/A* N/A* N/A* Example 164 2 0.22 Example 165 0.4 0.3 4 Example 166 0.8 1 12 Example 167 0.4 1 3 Example168 4 5 33 Example 169 10 1 1 Example 170 3 0.3 0.3 Example 171 0.9 0.10.1 Example 172 30 2 4 Example 173 5 11 177 Example 174 1 3 40 Example175 0.2 1 10 Example 176 5 12 108 Example 177 11 18 187 Example 178 0.52 15 Example 179 1 3 35 Example 180 2 3 39 Example 181 2 4 52 Example182 0.3 1 15 Example 183 1 1 9 Example 184 1 2 36 Example 185 41 77 1000Example 186 0.9 2 26 Example 187 19 34 1000 Example 188 0.1 0.1 3Example 189 12 27 246 Example 190 7 15 148 Example 191 0.5 2 19 Example192 0.6 2 17 Example 193 0.6 1 20 Example 194 0.3 1 8 Example 195 0.20.2 4 Example 196 1 5 43 Example 197 0.2 1 6 Example 198 3 11 79 Example199 0.2 1 2 Example 200 78 108 1000 Example 201 0.02 1 4 Example 202 0.31 6 Example 203 0.1 1 4 Example 204 0.1 0.3 1 Example 205 8 28 119Example 206 1 8 26 Example 207 0.3 1 3 Example 208 0.1 0.3 1 Example 2098 25 68 Example 210 0.5 2 8 Example 211 0.7 2 10 Example 212 4 14 112Example 213 1 2 8 Example 214 0.1 1 2 Example 215 1 18 51 Example 216 16 19 Example 217 0.3 12 23 Example 218 1 13 29 Example 219 1 9 36 N/A*:Not available. Prodrug of example 75

Test C: Estrogen Receptor Degradation Activity

Test C involves measuring the in vitro degradation activity of acompound of formula (I).

The measurements of the degradation activities were made using a breastcancer cell ERα in cell western assay as described hereunder.

MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated)at concentration of 10000 cells/30 μL per well in red phenol free MEMalpha medium (Invitrogen) containing 5% charcoal dextran striped FBS.The following day, 9 points serial 1:5 dilution of each compound wereadded to the cells in 2.5 μL at final concentrations ranging from3-0.000018 μM or 0.1 μM for fulvestrant (using as positive control). At4 hours post compounds addition the cells were fixed by adding 25 μL offormalin (final concentration 5% formalin containing 0.1% triton) for 10minutes at room temperature and then washed twice with PBS. Then, 50 μLof LI-COR blocking buffer containing 0.1% Triton was added to plate for30 minutes at room temperature. LI-COR blocking buffer was removed andcells were incubated overnight at cold room with 50 μL anti-ER rabbitmonoclonal antibody (Thermo scientific MA1-39540) diluted at 1:1000 inLI-COR blocking buffer containing 0.1% tween-20. Wells which weretreated with blocking but no antibody were used as background control.Wells were washed twice with PBS (0.1% tween-20) and incubated at 37° C.for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbitantibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 μM finalconcentration). Cells were then washed 3 times in PBS and scanned inACUMEN explorer (TTP-Labtech). Integrated intensities in the greenfluorescence and red fluorescence were measured to determine the levelsof ERα and DNA respectively.

The degradation activity with respect to estrogen receptors in this testis given by the concentration which degrades 50% of the estrogenreceptor (or IC50) in nM.

The % of ERα levels decrease were determined as follows: %inhibition=100*(1−(sample−fulvestrant: DMSO−fulvestrant)).

The Table 4 below indicates the estrogen receptor degradation activityresults for compounds of formula (I), and demonstrates that compoundstested have a significant degradation activity on estrogen receptors.

TABLE 4 Degradation % Degradation Examples IC₅₀ (nM) At 3 μM Example 10.4 88 Example 2 0.4 97 Example 3 3 82 Example 4 0.3 90 Example 5 0.3 93Example 6 0.7 90 Example 7 0.5 97 Example 8 0.5 96 Example 9 0.7 95Example 10 0.2 92 Example 11 0.7 89 Example 12 0.5 82 Example 13 0.5 91Example 14 0.3 94 Example 15 0.2 95 Example 16 2 90 Example 17 0.8 83Example 18 0.9 90 Example 19 1 82 Example 20 0.2 87 Example 21 0.2 83Example 22 2 81 Example 23 2 82 Example 24 28 86 Example 25 38 91Example 26 11 92 Example 27 2 91 Example 28 1 92 Example 29 0.4 88Example 30 2 82 Example 31 1 91 Example 32 2 87 Example 33 0.6 86Example 34 1 83 Example 35 0.8 89 Example 36 0.4 90 Example 37 1 95Example 38 1 96 Example 39 0.5 91 Example 40 0.2 88 Example 41 0.3 85Example 42 0.3 84 Example 43 0.2 83 Example 44 0.2 80 Example 45 0.2 93Example 46 0.2 94 Example 47 0.4 90 Example 48 0.2 96 Example 49 0.2 94Example 50 0.4 92 Example 51 0.2 98 Example 52 0.4 92 Example 53 8 95Example 54 0.2 92 Example 55 5 87 Example 56 2 85 Example 57 0.5 86Example 58 0.7 84 Example 59 0.4 86 Example 60 1 84 Example 61 1 86Example 62 0.7 96 Example 63 0.3 95 Example 64 0.4 88 Example 65 0.8 89Example 66 0.6 90 Example 67 2 92 Example 68 1 92 Example 69 0.2 87Example 70 0.7 80 Example 71 0.6 83 Example 72 2 88 Example 73 0.4 86Example 74 0.4 84 Example 75 2 84 Example 76 0.3 88 Example 77 0.3 83Example 78 0.9 92 Example 79 0.9 84 Example 80 1 90 Example 81 0.6 83Example 82 0.5 83 Example 83 2 80 Example 84 2 92 Example 85 1 92Example 86 0.7 89 Example 87 0.4 90 Example 88 0.5 86 Example 89 0.6 84Example 90 1 83 Example 91 0.2 86 Example 92 2 89 Example 93 0.3 86Example 94 2 88 Example 95 1 84 Example 96 1 86 Example 97 0.7 95Example 98 1 86 Example 99 0.9 94 Example 100 3 93 Example 101 1 87Example 102 0.6 87 Example 103 1 86 Example 104 0.6 84 Example 105 0.393 Example 106 2 87 Example 107 2 89 Example 108 0.2 87 Example 109 0.580 Example 110 0.8 83 Example 111 0.3 84 Example 112 0.6 88 Example 1130.2 90 Example 114 0.2 88 Example 115 0.2 89 Example 116 0.2 85 Example117 0.2 85 Example 118 0.2 87 Example 119 0.2 81 Example 120 0.2 85Example 121 0.2 87 Example 122 0.2 85 Example 123 0.2 83 Example 124 0.287 Example 125 0.2 93 Example 126 0.2 86 Example 127 0.2 89 Example 1281 82 Example 129 0.2 90 Example 130 0.2 80 Example 131 0.2 84 Example132 0.3 89 Example 133 0.2 88 Example 134 0.2 87 Example 135 0.2 85Example 136 0.2 82 Example 137 0.2 85 Example 138 0.3 88 Example 139 0.280 Example 140 0.2 86 Example 141 0.2 84 Example 142 0.2 84 Example 1430.2 81 Example 144 2 86 Example 145 0.2 83 Example 146 0.2 83 Example147 0.2 88 Example 148 0.2 83 Example 149 0.2 82 Example 150 1 82Example 151 1 81 Example 152 0.2 80 Example 153 0.2 91 Example 154 0.287 Example 155 0.2 89 Example 156 0.2 85 Example 157 0.2 81 Example 1580.2 82 Example 159 0.7 84 Example 160 0.2 83 Example 161 0.2 81 Example162 0.2 82 Example 163 N/A* N/A* Example 164 0.2 88 Example 165 0.2 82Example 166 0.5 86 Example 167 0.2 81 Example 168 0.6 91 Example 169 187 Example 170 0.5 82 Example 171 0.3 83 Example 172 2 80 Example 173 985 Example 174 0.7 92 Example 175 0.2 88 Example 176 2 81 Example 177 892 Example 178 0.2 94 Example 179 0.9 94 Example 180 3 91 Example 181 394 Example 182 0.2 93 Example 183 0.7 98 Example 184 2 95 Example 185 980 Example 186 0.9 87 Example 187 15 90 Example 188 0.2 91 Example 18922 90 Example 190 7 80 Example 191 0.5 89 Example 192 0.3 88 Example 1930.2 88 Example 194 0.8 90 Example 195 0.2 87 Example 196 8 86 Example197 0.6 92 Example 198 3 81 Example 199 0.2 95 Example 200 15 85 Example201 0.3 90 Example 202 0.2 84 Example 203 0.2 81 Example 204 0.2 82Example 205 4 88 Example 206 1 85 Example 207 0.2 86 Example 208 0.2 94Example 209 8 91 Example 210 1 91 Example 211 0.3 95 Example 212 2 94Example 213 0.2 96 Example 214 0.5 92 Example 215 1.5 80 Example 216 390 Example 217 2 90 Example 218 3 92 Example 219 1 89 N/A*: Notavailable. Prodrug of example 75

It is therefore apparent that the compounds of formula (I), or apharmaceutically acceptable salt thereof, have antagonist anddegradation activities for estrogen receptors, as well asantiproliferative activity. The compounds of formula (I), or apharmaceutically acceptable salt thereof, can therefore be used forpreparing medicaments, especially medicaments which are antagonists anddegraders of estrogen receptors.

Accordingly, also provided are medicaments which comprise a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof.

Another aspect is the compounds of formula (I) defined above, or apharmaceutically acceptable salt thereof, for use in therapy, especiallyas inhibitors and degraders of estrogen receptors.

Another aspect is the compounds of formula (I) defined above, or apharmaceutically acceptable salt thereof, for use in the treatment ofovulatory dysfunction, cancer, endometriosis, osteoporosis, benignprostatic hypertrophy or inflammation.

A particular aspect are the compounds of formula (I) defined above, or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer.

In an embodiment, the cancer is a hormone dependent cancer.

In another embodiment, the cancer is an estrogen receptor dependentcancer, particularly the cancer is an estrogen receptor a dependentcancer.

In another embodiment, the cancer is a cancer with wild type estrogenreceptors.

In another embodiment, the cancer is a cancer with deregulated functionof estrogen receptors related to, but not limited to, at least oneepigenetic and genetic alteration of estrogen receptors such usmutation, amplification, splice variant.

In another embodiment, the cancer is a cancer with mutated estrogenreceptors.

In another embodiment, the mutations of estrogen receptors can include,but not limited to, new or known mutations such us Leu536Arg, Tyr537Ser,Tyr537Asn, Asp538Gly.

In another embodiment, the cancer is an estrogen-sensitive cancer.

In another embodiment, the cancer is selected from breast, ovarian,endometrial, prostate, uterine, cervical and lung cancer, or ametastasis thereof.

In another embodiment, the metastasis is a cerebral metastasis.

In another embodiment, the cancer is breast cancer. Particularly, thebreast cancer is an estrogen receptor positive breast cancer (ERαpositive breast cancer).

In another embodiment, the cancer is resistant to anti-hormonaltreatment.

In a further embodiment, the anti-hormonal treatment is as single agentor in combination with other agents such as CDK4/6 or PI3K inhibitors.

In a further embodiment, the anti-hormonal treatment includes treatmentwith at least one agent selected from tamoxifen, fulvestrant, asteroidal aromatase inhibitor, and a non-steroidal aromatase inhibitor.

Another embodiment is a method of treating the pathological conditionsindicated above, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof. In an embodiment of thismethod of treatment, the subject is a human.

Another aspect is the use of a compound of the formula (I), or apharmaceutically acceptable salt thereof, for the manufacture of amedicament useful in treating any of the pathological conditionsindicated above, more particularly the use in treating cancer.

Another aspect is a pharmaceutical composition comprising as activeprinciple a compound of formula (I) or a pharmaceutically acceptablesalt thereof. These pharmaceutical compositions comprise an effectivedose of at least one compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and also at least one pharmaceuticallyacceptable excipient.

The said excipients are selected, in accordance with the pharmaceuticalform and method of administration desired, from the customaryexcipients, which are known to a person skilled in the art.

In the pharmaceutical compositions provided herein for oral, sublingual,subcutaneous, intramuscular, intravenous, topical, local,intra-tracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its base, acid, zwitterion orsalt thereof, may be administered in a unit administration form, in amixture with conventional pharmaceutical excipients, to animals and tohuman beings for the treatment of the above disorders or diseases.

The unit administration forms appropriate include oral forms such astablets, soft or hard gel capsules, powders, granules and oral solutionsor suspensions, sublingual, buccal, intra-tracheal, intra-ocular andintra-nasal administration forms, forms for inhalative, topical,transdermal, subcutaneous, intra-muscular or intravenous administration,rectal administration forms and implants. For topical application it ispossible to use the compounds of formula (I), or a pharmaceuticallyacceptable salt thereof, in creams, gels, ointments or lotions.

As an example, a unit administration form of a compound of formula (I)in tablet form may comprise the following components:

Compound of formula (I)  50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose   6.0 mg Corn starch  15.0 mgHydroxypropylmethylcellulose  2.25 mg Magnesium stearate   3.0 mg

There may be particular cases in which higher or lower dosages areappropriate. According to usual practice, the dosage that is appropriatefor each patient is determined by the doctor according to the mode ofadministration and the weight and response of the said patient.

1. A compound of formula (I):

wherein: R1 and R2 represent independently a hydrogen atom or adeuterium atom; R3 represents a hydrogen atom, a —COOH group, a —OHgroup, or a —OPO(OH)₂ group; R4 represents a hydrogen atom or a fluorineatom; R5 represents a hydrogen atom or a —OH group; wherein: at leastone of R3 or R5 is different from a hydrogen atom; when R3 represents a—COOH group, a —OH group or a —OPO(OH)₂ group, then R5 represents ahydrogen atom; and when R5 represents a —OH group, then R3 and R4represent hydrogen atoms; R6 is selected from the group consisting of aphenyl group or a heteroaryl group comprising 3 to 9 carbon atoms andcomprising from 1 to 3 heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulphur, said phenyl and heteroarylgroups being unsubstituted or substituted with 1 to 3 substituentsindependently selected from the group consisting of a (C₁-C₆)-alkylgroup unsubstituted or substituted with one or more fluorine atoms; ahalogen atom; a —OH group; a (C₁-C₆)-alkoxy group unsubstituted orsubstituted with one or more fluorine atoms; a cyano group; a sulphurgroup substituted with 5 fluorine atoms or (C₁-C₆)-alkyl groupssubstituted with two or more fluorine atoms; a sulfonyl-(C₁-C₆)-alkylgroup wherein said (C₁-C₆)-alkyl group is unsubstituted or substitutedwith two or more fluorine atoms; a silane group substituted with 3(C₁-C₆)-alkyl groups; an amine group unsubstituted or substituted withone or more (C₁-C₆)-alkyl groups; an amide group unsubstituted orsubstituted with one or more (C₁-C₆)-alkyl groups; a heterocycloalkylgroup saturated or partially saturated, comprising 3 to 5 carbon atomsand comprising 1 or 2 heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulphur; and a heteroaryl groupcomprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulphur andbeing unsubstituted or substituted with an oxo group; and a cycloalkylgroup or a heterocycloalkyl group comprising 4 to 9 carbon atoms andcomprising 1 or 2 heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulphur, said cycloalkyl orheterocycloalkyl groups being saturated or partially saturated and beingunsubstituted or substituted with 1 to 4 substituents independentlyselected from the group consisting of a fluorine atom; a —OH group; a(C₁-C₆)-alkyl group; a —COOR7 group wherein R7 is an (C₁-C₆)-alkylgroup; and an oxo group; or a pharmaceutically acceptable salt thereof.2. The compound of formula (I) according to claim 1, wherein R6 is aphenyl group unsubstituted or substituted with 1 to 3 substituentsindependently selected from the group consisting of a (C₁-C₆)-alkylgroup unsubstituted or substituted with one or more fluorine atoms; ahalogen atom; a —OH group; a (C₁-C₆)-alkoxy group unsubstituted orsubstituted with one or more fluorine atoms; a cyano group; a sulphurgroup substituted with 5 fluorine atoms or (C₁-C₆)-alkyl groupssubstituted with two or more fluorine atoms; a sulfonyl-(C₁-C₆)-alkylgroup wherein said (C₁-C₆)-alkyl group is unsubstituted or substitutedwith two or more fluorine atoms; a silane group substituted with 3(C₁-C₆)-alkyl groups; an amine group unsubstituted or substituted withone or more (C₁-C₆)-alkyl groups; an amide group unsubstituted orsubstituted with one or more (C₁-C₆)-alkyl groups; a heterocycloalkylgroup saturated or partially saturated, comprising 3 to 5 carbon atomsand comprising 1 or 2 heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulphur; and a heteroaryl groupcomprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulphur andbeing unsubstituted or substituted with an oxo group; or apharmaceutically acceptable salt thereof.
 3. The compound of formula (I)according to claim 1, wherein R6 is a phenyl group unsubstituted orsubstituted with 1 to 3 substituents independently selected from thegroup consisting of a methyl group; an ethyl group; an isopropyl group;a tert-butyl group; a —CHF₂ group; a —CF₃ group; a —CF₂CH₃ group; achlorine atom; a fluorine atom; a —OH group; a —OCH₃ group; a —OCH₂CH₃group; a —OCH₂CH₂F group; a —OCHF₂ group; a —OCH₂CF₂ group; a —OCF₃group; a —OCH₂CF₃ group; a cyano group; a —SCHF₂ group; a —SCF₃ group; a—SF₅ group; a —SO₂CH₃ group; a —SO₂CF₃ group; a —Si(CH₃)₃ group; anoxetane group; a piperidine group; a morpholine group; a pyrrolidinegroup; and a triazolone group; or a pharmaceutically acceptable saltthereof.
 4. The compound of formula (I) according to claim 1, wherein R3is a —COOH group or a —OH group; or a pharmaceutically acceptable saltthereof.
 5. A compound5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol;or a pharmaceutically acceptale salt thereof.
 6. A compound6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid; or a pharmaceuticallyacceptale salt thereof.
 7. A compound5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;or a pharmaceutically acceptale salt thereof.
 8. A compound6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;or a pharmaceutically acceptale salt thereof.
 9. A compound6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol;or a pharmaceutically acceptale salt thereof.
 10. A compound[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate; or a pharmaceutically acceptale salt thereof.11.-12. (canceled)
 13. A pharmaceutical composition comprising acompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.
 14. A pharmaceutical composition comprising5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol,or a pharmaceutically acceptale salt thereof, and at least onepharmaceutically acceptable excipient.
 15. A pharmaceutical compositioncomprising6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylicacid, or a pharmaceutically acceptale salt thereof, and at least onepharmaceutically acceptable excipient.
 16. A pharmaceutical compositioncomprising5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol,or a pharmaceutically acceptale salt thereof, and at least onepharmaceutically acceptable excipient.
 17. A pharmaceutical compositioncomprising6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol,or a pharmaceutically acceptale salt thereof, and at least onepharmaceutically acceptable excipient.
 18. A pharmaceutical compositioncomprising6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol,or a pharmaceutically acceptale salt thereof, and at least onepharmaceutically acceptable excipient.
 19. A pharmaceutical compositioncomprising[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate, or a pharmaceutically acceptale salt thereof, andat least one pharmaceutically acceptable excipient. 20.-27. (canceled)